Thieno(3,2-d)pyrimidines and furano(3,2-d)pyramidines and their use as purinergic receptor antagonists

ABSTRACT

A compound of formula (I), wherein X is S or O; R 1  is selected from H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR 5 , CO 2 R 5 , CONR 5 R 7 , CONR 5 NR 6 R 7 , NR 6 R 7 , NR 5 CONR 6 R 7 , NR 5 COR 6 , NR 5 CO 2 R 8 , and NR 5 SO 2 R 8 ; R 2  is selected from aryl attached via an unsaturated carbon atom; R 3  is selected from H, alkyl, hydroxy, alkoxy, halogen, CN and NO 2 ; R 3  is selected from H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO 2 , COR 5 , CO 2 R 5 , CONR 6 R 7 , CONR 5 NR 6 R 7 , NR 6 R 7 , NR 5 CONR 6 R 7 , NR 5 COR 6 , NR 5 CO 2 R 8  and NR 5 SO 2 R 8 ; R 5 , R 6  and R 7  are independently selected from H, alkyl and aryl or where R 6  and R 7  are in an (NR 6 R 7 ) group, R 6  and R 7  may be linked to form a heterocyclic group, or where R 5 , R 6  and R 7  are in a (CONR 5 NR 6 R 7 ) group, R 5  and R 6  may be linked to form a heterocyclic group; and R 8  is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, and the use thereof in therapy and in the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A 2A  receptors, may be beneficial, particularly wherein said disorder is a movement disorder such a Parkinson&#39;s disease or said disorder is depression, cognitive or memory impairment, acute or chronic pain, ADHD or narcolepsy, or wherein said medicament is for neuroprotection in a subject.

The present invention relates to thieno(3,2-d)pyrimidines and furano(3,2-d)pyrimidines and their use in therapy. In particular, the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial. The invention relates in particular to blockade of adenosine receptors and particularly adenosine A_(2A) receptors, and to the treatment of movement disorders such as Parkinson's disease.

Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.

There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson's disease are manifested.

Current strategies for the treatment of Parkinson's disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g. Deprenyl®), dopamine receptor agonists (e.g. bromocriptine and apomorphine) and anticholinergics (e.g. benztrophine, orphenadrine). Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when “on-off” symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients. Despite new drug approvals, there is still a medical need in terms of improved therapies for movement disorders, especially Parkinson's disease. In particular, effective treatments requiring less frequent dosing, effective treatments which are associated with less severe side-effects, and effective treatments which control or reverse the underlying neurodegenerative disorder, are required.

Blockade of A₂ adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson's disease (Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65). The potential utility of adenosine A_(2A) receptor antagonists in the treatment of movement disorders such as Parkinson's Disease has recently been reviewed (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320).

Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407-422). This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. Exp. Opin. Ther. Patents 1995, 5, 547-558).

Adenosine receptors represent a subclass (P₁) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A₁, A_(2A), A_(2B) (of high and low affinity) and A₃ (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156). The adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128).

The design of P₁ receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Williams, M. and Burnstock, G. Purinergic Approaches Exp. Ther. (1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)

It has been speculated that xanthine derivatives such as caffeine may offer a form of treatment for attention-deficit hyperactivity disorder (ADHD). A number of studies have demonstrated a beneficial effect of caffeine on controlling the symptoms of ADHD (Garfinkel, B. D. et al., Psychiatry, 1981, 26, 395-401). Antagonism of adenosine receptors is thought to account for the majority of the behavioural effects of caffeine in humans and thus blockade of adenosine A_(2A) receptors may account for the observed effects of caffeine in ADHD patients. Therefore a selective A_(2A) receptor antagonist may provide an effective treatment for ADHD but without the unwanted side-effects associated with current therapy.

Adenosine receptors have been recognised to play an important role in regulation of sleep patterns, and indeed adenosine antagonists such as caffeine exert potent stimulant effects and can be used to prolong wakefulness (Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265-1268). Recent evidence suggests that a substantial part of the actions of adenosine in regulating sleep is mediated through the adenosine A_(2A) receptor (Satoh, S., et al., Proc. Natl. Acad. Sci., USA, 1996). Thus, a selective A_(2A) receptor antagonist may be of benefit in counteracting excessive sleepiness in sleep disorders such as hypersomnia or narcolepsy.

It has recently been observed that patients with major depression demonstrate a blunted response to adenosine agonist-induced stimulation in platelets, suggesting that a dysregulation of A_(2A) receptor function may occur during depression (Berk, M. et al, 2001, Eur. Neuropsychopharmacol. 11, 183-186). Experimental evidence in animal models has shown that blockade of A_(2A) receptor function confers antidepressant activity (El Yacoubi, M et al. Br. J. Pharmacol. 2001, 134, 68-77). Thus, A_(2A) receptor antagonists may offer a novel therapy for the treatment of major depression and other affective disorders in patients.

The pharmacology of adenosine A_(2A) receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364-372). One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A₂ adenosine receptors is the evidence of a functional link between adenosine A_(2A) receptors to dopamine D₂ receptors in the CNS. Some of the early studies (e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A₂ receptors decreases the affinity of dopamine D₂ receptors in rat striatal membranes. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7238-41) have been summarised in two more recent articles (Fuxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., [Proc. Int. Symp.], 5th (1995), 499-507. Editors: Belardinelli, Luiz; Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Trends Neurosci. 1997, 20, 482-487).

As a result of these investigations into the functional role of adenosine A_(2A) receptors in the CNS, especially in vivo studies linking A₂ receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991, 130, 1624; Mandbane, S, N. et al., Eur. J. Pharmacol. 1997, 328, 135-141) investigations have been made into agents which selectively bind to adenosine A_(2A) receptors as potentially effective treatments for Parkinson's disease.

While many of the potential drugs for treatment of Parkinson's disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A_(2A) antagonist therapy is that the underlying neurodegenerative disorder may also be treated. The neuroprotective effect of adenosine A_(2A) antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N.Y. Acad. Sci. 1997, 825 (Neuroprotective Agents), 30-48). In particular, compelling recent evidence suggests that blockade of A_(2A) receptor function confers neuroprotection against MPTP-induced neurotoxicity in mice (Chen, J-F., J. Neurosci. 2001, 21, RC143). In addition, several recent studies have shown that consumption of dietary caffeine, a known adenosine A_(2A) receptor antagonist, is associated with a reduced risk of Parkinson's disease in man (Ascherio, A. et al, Ann Neurol., 2001, 50, 56-63; Ross G W, et al., JAMA, 2000, 283, 2674-9). Thus, A_(2A) receptor antagonists may offer a novel treatment for conferring neuroprotection in neurodegenerative diseases such as Parkinson's disease.

Xanthine derivatives have been disclosed as adenosine A₂ receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A₂ receptors, such as Parkinson's disease (see, for example, EP-A-565377).

One prominent xanthine-derived adenosine A_(2A) selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323, 141-144).

Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A₁ and A_(2A) receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in Parkinson's disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T-.W. J. Pharm. Pharmacol. 1994, 46, 515-517).

KF 17837 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine] is a selective adenosine A_(2A) receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A_(2A) receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine. Moreover, KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A_(2A) receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A_(2A) receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268). The structure activity relationship (SAR) of KF 17837 has been published (Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352). Recent data has also been provided on the A_(2A) receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr. 1997, 23, 119.14; and Kanda, T. et al., Ann. Neurol. 1998, 43(4), 507-513).

New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective A_(2A) Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164-71). SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70) and has been followed up by a later series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998, 41(12), 2126-2133).

The foregoing discussion indicates that a potentially effective treatment for movement disorders in humans would comprise agents which act as antagonists at adenosine A_(2A) receptors.

It has now been found that thieno(3,2-d)pyrimidines and furano(3,2-d)pyrimidines, which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (P₁) receptors, and in particular at the adenosine A_(2A) receptor. Such compounds may therefore be useful for the treatment of disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial. In particular such compounds may be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias. Disorders of particular interest include Parkinson's disease, Alzheimer's disease, spasticity, Huntington's chorea and Wilson's disease.

Such compounds may also be particularly suitable for the treatment of depression, cognitive or memory impairment including Alzheimer's disease, acute or chronic pain, ADHD, narcolepsy or for neuroprotection.

According to the present invention there is provided a compound of formula (I):

wherein

X is S or O;

R₁ is selected from H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR₅, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇, NR₆R₇, NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈, and NR₅SO₂R₈; R₂ is selected from aryl attached via an unsaturated carbon atom; R₃ is selected from H, alkyl, hydroxy, alkoxy, halogen, CN and NO₂; R₄ is selected from H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO₂, COR₅, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇, NR₆R₇, NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈ and NR₅SO₂R₈; R₅, R₆ and R₇ are independently selected from H, alkyl and aryl, or where R₆ and R₇ are in an (NR₆R₇) group, R₆ and R₇ may be linked to form a heterocyclic group, or where R₅, R₆ and R₇ are in a (CONR₅NR₆R₇) group, R₅ and R₆ may be linked to form a heterocyclic group; and R₈ is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof.

As used herein, the term “alkyl” means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl)hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C₃ to C₁₂, more preferably C₅ to C₁₀, more preferably C₅, C₆ or C₇. Where acyclic, the alkyl group is preferably C₁ to C₁₀, more preferably C₁ to C₆, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl. It will be appreciated therefore that the term “alkyl” as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl.

As used herein, the term “lower alkyl” means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).

As used herein, the term “aryl” means an aromatic group, such as phenyl or naphthyl (preferably phenyl), or a heteroaromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl or pyrimidinyl.

As used herein, the term “heteroaryl” means an aromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl or pyrimidinyl.

As used herein, the term “alkoxy” means alkyl-O—. As used herein, the term “aryloxy” means aryl-O—.

As used herein, the term “halogen” means a fluorine, chlorine, bromine or iodine radical.

As used herein, the term “ortho,ortho-disubstituted aryl groups” refers to aryl groups which are substituted in both ortho positions of the aryl group relative to the point of attachment of the aryl group to the pyrimidine ring.

As used herein, the term “prodrug” means any pharmaceutically acceptable prodrug of a compound of the present invention.

Where any of R₁ to R₁₃ is selected from alkyl, alkoxy and thioalkyl, in accordance with formula (I) as defined above, then that alkyl group, or the alkyl group of the alkoxy or thioalkyl group, may be substituted or unsubstituted. Where any of R₁ to R₁₃ are selected from aryl, aryloxy and thioaryl, in accordance with formula (I) as defined above, then said aryl group, or the aryl group of the aryloxy or thioaryl group, may be substituted or unsubstituted. Where R₅ and R₆, or R₆ and R₇, or R₁₂ and R₁₃, or R₅ and R₁₂ are linked to form a heterocyclic group, the heterocyclic group may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include:

carbon-containing groups such as

-   -   alkyl,     -   aryl, (e.g. substituted and unsubstituted phenyl (including         alkylphenyl, alkoxyphenyl and halophenyl),     -   arylalkyl; (e.g. substituted and unsubstituted benzyl);         halogen atoms and halogen containing groups such as     -   haloalkyl (e.g. trifluoromethyl),     -   haloaryl (e.g. chlorophenyl);         oxygen containing groups such as     -   alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl,         (aryl)(hydroxy)alkyl),     -   ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl,         alkoxyaryl, aryloxyaryl),     -   aldehydes (e.g. carboxaldehyde),     -   ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl,         alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl,         arylalkylcarbonyl, arylalkylcarbonylalkyl,         arylalkylcarbonylaryl)     -   acids (e.g. carboxy, carboxyalkyl, carboxyaryl),     -   acid derivatives such as esters         -   (e.g. alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl,             aryloxycarbonylalkyl, alkoxycarbonylaryl,             aryloxycarbonylaryl, alkylcarbonyloxy,             alkylcarbonyloxyalkyl), amides         -   (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl,             cyclicaminocarbonyl, aminocarbonylalkyl, mono- or             di-alkylaminocarbonylalkyl, arylaminocarbonyl or             arylalkylaminocarbonyl, alkylcarbonylamino,             arylcarbonylamino or arylalkylcarbonylamino), carbamates         -   (eg. alkoxycarbonylamino, aryloxycarbonylamino,             arylalkyloxycarbonylamino, aminocarbonyloxy, mono- or             di-alkylaminocarbonyloxy, arylaminocarbonyloxy or             arylalkylaminocarbonyloxy)         -   and ureas         -   (eg. mono- or di-alkylaminocarbonylamino,             arylaminocarbonylamino or arylalkylaminocarbonylamino);             nitrogen containing groups such as     -   amines (e.g. amino, mono- or dialkylamino, cyclicamino,         arylamino, aminoalkyl, mono- or dialkylaminoalkyl),     -   azides,     -   nitriles (e.g. cyano, cyanoalkyl),     -   nitro,     -   sulfonamides (e.g. aminosulfonyl, mono- or         di-alkylaminosulfonyl, mono- or di-arylaminosulfonyl, alkyl- or         aryl-sulfonylamino, alkyl- or aryl-sulfonyl(alkyl)amino, alkyl-         or aryl-sulfonyl(aryl)amino);         sulfur containing groups such as     -   thiols, thioethers, sulfoxides, and sulfones         -   (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl,             alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,             arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl,             arylsulfinylalkyl, arylsulfonylalkyl);             heterocyclic groups containing one or more, preferably one,             heteroatom,     -   (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,         thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,         aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl,         imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl,         pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl,         hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl,         benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl,         indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl,         isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl,         cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,         quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl         and carbolinyl); and         silicon-containing groups such as     -   silanes (e.g. trialkylsilyl).

In one embodiment, where any of R₁ to R₁₃ is directly substituted by an alkyl substituent group, or by an alkyl-containing substituent group (such as alkoxy, alkoxyalkyl or alkylcarbonylamino for example), then the alkyl moiety of the substituent group directly attached to any of R₁ to R₁₃ may be further substituted by the substituent groups hereinbefore described and particularly by halogen, hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and aryl.

In a further embodiment, where any of R₁ to R₁₃ is directly substituted by an aryl substitutent group, or by an aryl-containing substituent group (such as aryloxy or arylaminocarbonylamino for example), then the aryl moiety of the substituent group directly attached to any of R₁ to R₁₃ may be further substituted by the substituent groups hereinbefore described and particularly by halogen, alkyl (including CF₃), hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and NO₂.

The terms “directly substituted” and “directly attached”, as used herein, mean that the substituent group is bound directly to any of R₁ to R₁₃ without any intervening divalent atoms or groups.

In the compounds of formula (I), it is preferred that X is S.

In the compounds of formula (I), R₁ is selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), aryl (including heteroaryl), hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR₅, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇, NR₆R₇ (including NH₂, monoalkyl amino and dialkylamino), NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈ and NR₅SO₂R₈.

It is preferred that R₁ is selected from alkyl, alkoxy, thioalkyl, NR₆R₇ and NR₅COR₆, and preferably from alkyl and NR₆R₇. In one embodiment, R₁ is selected from NH₂.

Where R₁ is selected from alkyl, alkoxy and alkylthio, then said alkyl group or the alkyl group of the alkoxy or alkylthio is preferably selected from C₁₋₆ alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), preferably saturated C₁₋₆ alkyl, and more preferably lower alkyl. In a preferred embodiment, R₁ is selected from substituted alkyl, particularly haloalkyl (including CF₃) and arylalkyl (including heteroarylalkyl).

In one embodiment, R₁ is selected from CONR₅NR₆R₇, NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈ and NR₅SO₂R₈, and R₅ is H or alkyl, and preferably H.

In one embodiment, R₁ is selected from NR₆R₇ wherein R₆ is preferably selected from H and alkyl (preferably H), and R₇ is a substituted alkyl group represented by (CR₉R₁₀)_(n)R₁₁, wherein R₉ and R₁₀ are independently selected from H, alkyl and aryl (preferably from H and alkyl, and more preferably from H), n is selected from 1 to 6 (preferably from 2 to 4, more preferably 2), and R₁₁ is selected from aryl (including heteroaryl), COR₅, CO₂R₅, CONR₁₂R₁₃, CONR₅NR₁₂R₁₃, NR₁₂R₁₃ (including NH₂, monoalkyl amino and dialkylamino), NR₅CONR₁₂R₁₃, NR₅COR₁₂, NR₅CO₂R₈ and NR₅SO₂R₈ (and preferably from aryl (including heteroaryl), NR₁₂R₁₃ (including NH₂, monoalkyl amino and dialkylamino), NR₅CONR₁₂R₁₃, NR₅COR₁₂, NR₅CO₂R₈ and NR₅SO₂R₉), wherein R₅ and R₈ are as hereinbefore defined and wherein R₁₂ and R₁₃ are independently selected from H, alkyl and aryl, or where R₁₂ and R₁₃ are in an (NR₁₂R₁₃) group, R₁₂ and R₁₃ may be linked to form a heterocyclic group, or where R₅, R₁₂ and R₁₃ are in a (CONR₅NR₁₂R₁₃) group, R₅ and R₁₂ may be linked to form a heterocyclic group.

In the compounds of formula (I), R₂ is substituted or unsubstituted aryl (including heteroaryl) attached via an unsaturated carbon atom. Preferably, the aryl group is a 5- or 6-membered monocyclic aryl group.

Preferably, R₂ is a heteroaryl group, and preferably a heteroaryl group which is attached to the pyrimidine ring of formula (I) such that a heteroatom is adjacent to the unsaturated carbon atom attached to said pyrimidine ring. Preferably, R₂ is an N, O or S-containing heteroaryl group. R₂ may contain one or more heteroatom(s) selected from N, O and S.

It is preferred that the aryl (including heteroaryl) group of R₂ is not ortho,ortho-disubstituted. Preferably, the aryl (including heteroaryl) group of R₂ is not substituted at either ortho position. As used herein, reference to ortho-substitution of the R₂ group means the ortho positions of the R₂ group relative to the point of attachment of R₂ to the pyrimidine moiety of formula (I).

In a preferred embodiment, R₂ is selected from furyl (including 2-furyl), thienyl (including 2-thienyl), pyridyl (including 2-pyridyl), thiazolyl (including 2- and 5-thiazolyl), pyrazolyl (including 3-pyrazolyl), triazolyl (including 4-triazolyl), pyrrolyl (including 2-pyrrolyl) and oxazolyl (including 5-oxazolyl). In a further embodiment, R₂ is selected from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl, 3-pyrazolyl, 2-pyrrolyl, 4-triazolyl and 5-oxazolyl. In a preferred embodiment, R₂ is selected from furyl, thienyl, pyridyl and thiazolyl, and preferably from 2-furyl, 2-thienyl, 2-thiazolyl and 2-pyridyl.

In a particularly preferred embodiment, R₂ is selected from 2-thiazolyl, optionally substituted, particularly by methyl.

In the compounds of formula (I), R₃ is selected from H, alkyl (including haloalkyl (particularly CF₃)), hydroxy, alkoxy (including OCF₃), halogen, CN and NO₂. Preferably, R₃ is selected from H, CF₃, hydroxy, alkoxy, halogen, CN and NO₂, and preferably R₃ is H.

In the embodiment where R₃ is selected from alkyl or alkoxy, then said alkyl group or the alkyl group of said alkoxy is preferably C₁₋₆ alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), preferably saturated C₁₋₆ alkyl, and more preferably lower alkyl. In a preferred embodiment of compounds wherein R₃ is selected from alkyl, R₃ is haloalkyl (particularly CF₃).

In the compounds of formula (I), R₄ is selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), aryl (including heteroaryl), hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO₂, COR₅, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇, NR₆R₇ (including NH₂), NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈ and NR₅SO₂R₈.

Where R₄ is selected from alkyl, preferably R₄ is C₁₋₆ alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, and cyclic and acyclic alkyl), preferably saturated C₁₋₆ alkyl, and more preferably lower alkyl. In one embodiment, R₄ is selected from substituted alkyl, wherein the substituent groups are selected from halogen, substituted and unsubstituted aryl (including heteroaryl), cycloalkyl, non-aromatic heterocyclyl, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇ and C(═NR₅)NR₆R₇, preferably aryl (including heteroaryl) and CONR₆R₇, more preferably aryl (including heteroaryl). In an alternative embodiment, R₄ is selected from substituted alkyl, particularly haloalkyl (including CF₃) and arylalkyl (including heteroarylalkyl). In an alternative embodiment, R₄ is selected from unsubstituted C₁₋₆ alkyl (preferably saturated C₁₋₆ alkyl).

In one embodiment R₄ is selected from H, alkyl (including arylalkyl (including heteroarylalkyl)), halogen, COR₅, CO₂R₅, CONR₆R₇ and CONR₅NR₆R₇, preferably from H, alkyl (including arylalkyl (including heteroarylalkyl)) and halogen, and preferably from H.

In the compounds of formula (I), R₅, R₆ and R₇ are independently selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl) and aryl (including heteroaryl), or where R₆ and R₇ are in any NR₆R₇ group R₆ and R₇ may be linked to form a heterocyclic group, or where R₅, R₆ and R₇ are in a CONR₅NR₆R₇ group, R₅ and R₆ may be linked to form a heterocyclic group.

In the compounds of formula (I), R₁₂ and R₁₃ are independently selected from H, alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl) and aryl (including heteroaryl), or where R₁₂ and R₁₃ are in any NR₁₂R₁₃ group R₁₂ and R₁₃ may be linked to form a heterocyclic group, or where R₅, R₁₂ and R₁₃ are in a CONR₅NR₁₂R₁₃ group, R₅ and R₁₂ may be linked to form a heterocyclic group.

In the compounds of formula (I), R₈ is selected from alkyl (including branched and unbranched alkyl, substituted and unsubstituted alkyl, cyclic and acyclic alkyl) and aryl (including heteroaryl).

Where R₅ to R₁₀, R₁₂ and R₁₃, are independently selected from alkyl, preferably R₅ to R₁₀, R₁₂ and R₁₃ are independently selected from C₁₋₆ alkyl, preferably C₁₋₆ saturated alkyl and more preferably from lower alkyl.

Where R₆ and R₇, or R₁₂ and R₁₃, are linked to form a heterocyclic ring, said heterocyclic ring may be saturated, partially unsaturated or aromatic, and is preferably saturated. Said heterocyclic ring is preferably a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring, and may contain one or more further heteroatom(s) preferably selected from N, O and S.

Where R₅ and R₆, or R₅ and R₁₂, are linked to form a heterocyclic ring, said heterocyclic ring may be saturated, partially unsaturated or aromatic, and is preferably saturated. Said heterocyclic ring is preferably a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring, and may contain one or more further heteroatom(s) preferably selected from N, O and S.

In a particularly preferred embodiment of the invention, the compounds of the present invention are selected from:

-   7-bromo-4-(2-furyl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine; -   N-allyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine; -   2-ethyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine; -   2-methyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine; -   2-n-propyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine; -   N-(2-hydroxyethyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine; -   2-isopropyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine; -   N-(2-methoxyethyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine; -   N,N-dimethyl-4-(4-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine; -   4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine; -   2-ethyl-4-(4-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine; -   2-ethyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine; -   N,N-dimethyl-4-(5-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine; -   N,N-dimethyl-4-(4,5-dimethyl-2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine; -   4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine; -   (2R)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine; -   N-allyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine; -   2-isopropyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine; -   N,N-dimethyl-4-(5-methyl-2-pyridyl)thieno[3,2-d]pyrimidine-2-amine; -   2-tert-butyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine; -   2-cyclopropyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine; -   2-ethyl-4-(6-methyl-2-pyridyl)thieno[3,2-d]pyrimidine; -   (2S)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine;     and -   2-(2-chloroethyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine.

Where chiral the compounds of the present invention may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.

According to a further aspect of the invention, there is provided for use in therapy a compound of the present invention, or a pharmaceutically acceptable salt or prodrug thereof.

The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.

The disorders of particular interest are those in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial. These may include movement disorders such as Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson's disease (punch-drunk syndrome).

Other movement disorders in which the blocking of purine receptors, may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in abnormal movement or posture. The present invention may also be effective in treating Parkinson's with on-off phenomena; Parkinson's with freezing (end of dose deterioration); and Parkinson's with prominent dyskinesias.

The compounds of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA or a dopamine agonist, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.

Other disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors may be beneficial include acute and chronic pain; for example neuropathic pain, cancer pain, trigeminal neuralgia, migraine and other conditions associated with cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain and HIV pain; affective disorders including mood disorders such as bipolar disorder, seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease; central and peripheral nervous system degenerative disorders including corticobasal degeneration, demyelinating disease (multiple sclerosis, disseminated sclerosis), Freidrich's ataxia, motoneurone disease (amyotrophic lateral sclerosis, progressive bulbar atrophy), multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathy (diabetic neuropathy, tabes dorsalis, drug-induced neuropathy, vitamin deficiency), systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy, spasticity; schizophrenia and related pyshoses; cognitive disorders including dementia, Alzheimers Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntingtons Disease, Lewy body dementia, senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome, dementia pugilans; attention disorders such as attention-deficit hyperactivity disorder (ADHD), attention deficit disorder, minimal brain dysfunction, brain-injured child syndrome, hyperkinetic reaction childhood, and hyperactive child syndrome; central nervous system injury including traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injury, raised intracranial pressure, cerebral oedema, hydrocephalus, spinal cord injury; cerebral ischaemia including transient ischaemic attack, stroke (thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke, lacunar stroke) subarachnoid haemorrhage, cerebral vasospasm, neuroprotection for stroke, peri-natal asphyxia, drowning, cardiac arrest, subdural haematoma; myocardial ischaemia; muscle ischaemia; sleep disorders such as hypersomnia and narcolepsy; eye disorders such as retinal ischaemia-reperfusion injury and diabetic neuropathy; cardiovascular disorders such as claudication and hypotension; and diabetes and its complications.

According to a further aspect of the present invention, there is provided the use of a compound of the present invention or a pharmaceutically acceptably salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A_(2A) receptors, may be beneficial.

According to a further aspect of the present invention there is provided a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial, the method comprising administration to a subject in need of such treatment an effective dose of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof.

The disorder may be caused by the hyperfunctioning of the purine receptors.

According to a further aspect of the present invention there is provided use of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of movement disorders in a subject.

According to a further aspect of the invention there is provided a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof.

According to a further aspect of the invention there is provided use of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.

According to a further aspect of the invention there is provided a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof.

The medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.

According to a further aspect of the invention, there is provided a method of preparing the novel compounds of the present invention. Compounds of formula (I) may be prepared according to conventional synthetic methods, such as set out in Reaction Scheme 1.

Compounds of formula (1) are prepared from halides of formula (2) by standard methods such as aryl coupling reactions which may be advantageously carried out in the presence of a catalyst such as a palladium catalyst. The aryl coupling reaction may be carried out by reaction of a halide of formula (2) with, for example, an aryl or heteroaryl trialkyltin reagent, an aryl or heteroaryl boronic acid or boronic ester reagent or an aryl or heteroaryl zinc halide reagent according to methods described in the literature. Suitable aryl or heteroaryl trialkyl tin, boronic acid, boronic ester or zinc halide reagents are either commercially available or may be prepared by standard literature methods.

Halides of formula (2) are either known in the literature or may be prepared from compounds of formula (3) by standard methods, for example by treatment with a chlorinating reagent such as POCl₃. Compounds of formula (3) are either known in the literature or may be prepared from compounds of formula (4) by standard methods such as treatment with an appropriate ester (R₁CO₂Et) in the presence of a suitable base such as NaOEt, or by treatment with an appropriate anhydride (R₁CO)₂O in the presence of a base such as Et₃N followed by heating in the presence of a stronger base such as NaOH. Alternatively compounds of formula (3) may be prepared from compounds of formula (5) by standard methods such as treatment with an appropriate nitrile (R₁CN) in the presence of dry HCl gas. Compounds of formula (4) and formula (5) are either known in the literature or may be prepared by standard methods.

Compounds of formula (1) where R₁ is NR₆R₇ may be prepared from compounds of formula (1) where R₁ is halogen by standard methods such as reaction with an appropriate amine (R₆R₇NH). Compounds of formula (1) where R₁ is halogen may be prepared from compounds of formula (2) where R₁ is halogen as described above. Compounds of formula (2) where R₁ is halogen are either known in the literature or may be prepared by methods analogous to those described in the literature.

Compounds of formula (1) where R₁ is NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈ or NR₅SO₂R₈ wherein R₅ is H may be prepared from compounds of formula (1) where R₁ is NH₂ by standard methods for example by treatment with an appropriate isocyanate (R₆NCO or R₇NCO), carbamoyl chloride (R₆R₇NCOCl), acid chloride (R₆COCl), chloroformate (ClCO₂R₈) or sulphonyl chloride (ClSO₂R₈). Analogous compounds wherein R₅ is alkyl may be prepared by initial alkylation or reductive alkylation followed by reaction with the appropriate reagent as described above.

Compounds of formula (1) where R₁ is NH₂ may be prepared from compounds of formula (1) where R₁ is halogen either by direct displacement with ammonia or by reaction with an appropriate protected amine, for example 3,4-dimethoxybenzylamine, followed by removal of the protecting group, if desired, by treatment with TFA.

Compounds of formula (1) where R₁ is hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, or CN may be prepared from compounds of formula (1) where R₁ is halogen by direct displacement with an appropriate nucleophile such as water, an alcohol, thiol or cyanide in the presence of a suitable base.

Compounds of formula (1) where R₁ is CONR₆R₇ or CONR₅NR₆R₇ may be prepared from compounds of formula (1) where R₁ is CO₂R₅ by standard methods such as reaction with an appropriate amine (R₆R₇NH) or substituted hydrazine (HNR₅NR₆R₇), either directly or in the presence of a suitable reagent such as trimethylaluminium.

Compounds of formula (1) where R₁ is COR₅, wherein R₅ is H, may be prepared from compounds of formula (1) where R₁ is CO₂R₅ by standard methods such as reduction with an appropriate reducing agent such as DIBAL at low temperature. Compounds of formula (1) where R₁ is COR₅, wherein R₅ is alkyl or aryl, may be prepared from compounds of formula (1) where R₁ is COR₅, wherein R₅ is H, by standard methods such as initial treatment with an appropriate alkyl or arylithium or Grignard reagent, followed by oxidation.

Compounds of formula (1) where R₁ is CO₂R₅ may be prepared according to Reaction Scheme 1 by the methods described above.

In a compound of formula (1) where R₁ is alkyl or aryl or where the group R₁ contains an alkyl or aryl substituent, the alkyl or aryl group may be substituted as defined above. Where the alkyl or aryl group is substituted by a reactive functional group it will be appreciated that derivatisation of the reactive functional group may lead to a wide variety of additional substituent groups. By way of example where the alkyl or aryl group is substituted by an amino group then the amino group may be derivatised to form a mono- or dialkylamine, urea, thiourea, amide, carbamate or sulphonamide by the use of standard reactions such as those described above. Where the alkyl or aryl group is substituted by an amino group it may be advantageous to protect the amino group during the synthesis by the use of a standard protecting group such as a BOC group. The protecting group may then be removed at the appropriate step in the synthesis, by standard methods such as treatment with TFA.

Compounds of formula (1) where R₃ is halogen or NO₂ may be prepared from compounds of formula (2) where R₃ is halogen or NO₂ as described above. Compounds of formula (2) where R₃ is halogen or NO₂ are either known in the literature or may be prepared from compounds of formula (2) where R₃ is H by standard literature methods such as halogenation or nitration.

Compounds of formula (1) where R₃ is hydroxy, alkoxy or cyano may be prepared from compounds of formula (2) where R₃ is hydroxy, alkoxy or cyano as described above. Compounds of formula (2) where R₃ is hydroxy, alkoxy or cyano may be prepared from compounds of formula (2) where R₃ is halogen by standard literature methods such as nucleophilic displacement.

Compounds of formula (1) where R₄ is aryl or heteroaryl may be prepared from compounds of formula (1) where R₄ is halogen by standard methods such as palladium catalysed aryl coupling reactions as described above. Compounds of formula (1) where R₄ is halogen are prepared from compounds of formula (2) where R₄ is halogen as described above. Compounds of formula (2) where R₄ is halogen are either known in the literature or prepared by methods analogous to those described in the literature.

Compounds of formula (1) where R₄ is NH₂ are prepared from compounds of formula (1) where R₄ is NO₂ by standard methods such as reduction. Compounds of formula (1) where R₄ is NO₂ are prepared from compounds of formula (2) where R₄ is NO₂ as described above. Compounds of formula (2) where R₄ is NO₂ are either known in the literature or prepared by methods analogous to those described in the literature.

Compounds of formula (1) where R₄ is NR₆R₇, NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈ or NR₅SO₂R₈ wherein R₅ is H may be prepared from compounds of formula (1) where R₄ is NH₂ by standard methods for example by mono- or dialkylation, reductive alkylation or by treatment with an appropriate isocyanate (R₆NCO or R₇NCO), carbamoyl chloride (R₆R₇NCOCl), acid chloride (R₆COCl), chloroformate (ClCO₂R₈) or sulphonyl chloride (ClSO₂R₈). Analogous compounds wherein R₅ is alkyl may be prepared by initial alkylation or reductive alkylation followed by reaction with the appropriate reagent as described above.

Compounds of formula (1) where R₄ is COR₅ may be prepared from compounds of formula (2) where R₄ is COR₅ as described above. Compounds of formula (2) where R₁ is COR₅ may be prepared from compounds of formula (2) where R₄ is H by standard methods such as Friedel-Crafts acylation.

Compounds of formula (1) where R₄ is CO₂R₅, CONR₆R₇ or CONR₅NR₆R₇ may be prepared from compounds of formula (2) where R₄ is CO₂R₅, CONR₆R₇ or CONR₅NR₆R₇ as described above. Compounds of formula (2) where R₄ is CO₂R₅ or CONR₆R₇ may be prepared from compounds of formula (2) where R₄ is halogen by standard methods such as palladium catalysed carbonylation reactions in the presence of an appropriate alcohol (R₅OH) or amine (HNR₆R₇). Compounds of formula (2) where R₄ is CONR₆R₇ or CONR₅NR₆R₇ may be prepared from compounds of formula (2) where R₄ is CO₂R₅ by standard methods such as reaction with a suitable amine (HNR₆R₇) or hydrazine (HNR₅NR₆R₇) derivative.

Compounds of formula (1) where R₄ is cyano may be prepared from compounds of formula (1) where R₄ is CONR₆R₇, wherein R₆ and R₇ are both H, by standard literature methods such as dehydration.

Compounds of formula (1) where R₄ is hydroxy, alkoxy, aryloxy, thioalkyl or thioaryl may be prepared by standard literature methods known to those skilled in the art. Such standard methods may include treatment of a compound of formula (1) where R₄ is halogen with an appropriate nucleophile. Alternatively compounds of formula (1) where R₄ is hydroxy or alkoxy may be prepare from a compound of formula (1) where R₄ is COR₅ by use of the Bayer Villiger reaction, followed by a hydrolysis step and followed, if desired, by an alkylation step.

According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or excipient.

The pharmaceutical compositions employed in the present invention comprise a compound of the present invention, or pharmaceutically acceptable salts or prodrugs thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art. The term, “pharmaceutically acceptable salts”, refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.

Where the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.

Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of the present invention. For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The most suitable route in any given case will depend on the severity of the condition being treated. The most preferred route of administration of the present invention is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practical use, the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.

In addition to the common dosage forms set out above, the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.

Pharmaceutical compositions employed in the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practised without departing from the purpose and interest of this invention.

EXAMPLES Synthetic Examples

The invention is illustrated with reference to the following Examples, as set out in Table 1. The syntheses of the Examples are performed using the general Synthetic Methods described hereinafter. The Method used for each Example is given in parentheses in column 1 of Table 1. Analytical data are given in Table 2.

TABLE 1 Example Structure Compound Name 1(A)

2-chloro-4-(2-thienyl)thieno[3,2-d]pyrimidine 2(E)

N,N-dimethyl-4-(2-thienyl)thieno[3,2-d]pyrimidine-2-amine 3(A)

2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine 4(E)

(2R)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2-thienyl)thieno[3,2-d]pyrimidine 5(E)

N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 6(E)

N-(3-(1H-imidazol-1-yl)propyl)-4-(2-thienyl)thieno[3,2-d]pyrimidine-2-amine 7(E)

N-(2-hydroxyethyl)-4-(2-thienyl)thieno[3,2-d]pyrimidine-2-amine 8(E)

2-methoxy-4-(2-thienyl)thieno[3,2-d]pyrimidine 9(B)

2-ethyl-4-(2-thienyl)thieno[3,2-d]pyrimidine 10(E)

N-(3-(1H-imidazol-1-yl)propyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 11(A)

4-(2-furyl)-2-trifluoromethylthieno[3,2-d]pyrimidine 12(A)

2-chloro-4-(2-furyl)-7-methylthieno[3,2-d]pyrimidine 13(A)

7-bromo-2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine 14(E)

4-(2-furyl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine 15(E)

7-bromo-4-(2-furyl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine 16(E)

4-(2-furyl)-N-(2-hydroxyethyl)-7-methylthieno[3,2-d]pyrimidine-2-amine 17(A)

4-(2-benzothiophenyl)-2-chlorothieno[3,2-d]pyrimidine 18(A)

2-ethyl-4-(2-furyl)thieno[3,2-d]pyrimidine 19(E)

4-(2-benzothiophenyl)-N,N-dimethylthieno[3,2-d]pyrimidine-2-amine 20(E)

4-(2-benzothiophenyl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine 21(E)

N-ethyl-4-(2-thienyl)thieno[3,2-d]pyrimidine-2-amine 22(E)

7-bromo-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 23(E)

4-(2-furyl)-7,N,N-trimethylthieno[3,2-d]pyrimidine-2-amine 24(A)

2-chloro-4-(2-pyridyl)thieno[3,2-d]pyrimidine 25(E)

4-(2-furyl)-2-morpholinothieno[3,2-d]pyrimidine 26(E)

N-benzyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 27(E)

N,N-dimethyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine-2-amine 28(B)

2-chloro-4-(1H-pyrrol-1-yl)thieno[3,2-d]pyrimidine 29(A)

Ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-acetate 30(A)

2-chloro-4-(2-pyrazinyl)thieno[3,2-d]pyrimidine 31(P)

4,7-bis(2-furyl)-N,N-dimethylthieno[3,2-d]pyrimidine-2-amine 32(E)

N,N-dimethyl-4-(1H-pyrrol-1-yl)thieno[3,2-d]pyrimidine-2-amine 33(E)

N,N-dimethyl-4-(2-pyrazinyl)thieno[3,2-d]pyrimidine-2-amine 34(E)

N-(2-hydroxyethyl)-4-(2-pyrazinyl)thieno[3,2-d]pyrimidine-2-amine 35(E)

4-(2-furyl)-2-(4-methylpiperazinyl)thieno[3,2-d]pyrimidine 36(E)

4-(2-furyl)-2-isopropylthiothieno[3,2-d]pyrimidine 37(E)

2-ethylthio-4-(2-furyl)thieno[3,2-d]pyrimidine 38(E)

(2R)-4-(2-furyl)-2-(2-hydroxymethylpyrrolidin-1-yl)thieno[3,2-d]pyrimidine 39(E)

4-(2-furyl)-2-methylthiothieno[3,2-d]pyrimidine 40(E)

N-allyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 41(A)

2-chloro-4-(2-furyl)-7-nitrothieno[3,2-d]pyrimidine 42(E)

N-ethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 43(E)

4-(2-furyl)-2-(pyrrolidin-1-yl)thieno[3,2-d]pyrimidine 44(E)

N,N-dimethyl-4-(2-furyl)-7-nitrothieno[3,2-d]pyrimidine-2-amine 45(E)

4-(2-furyl)-N-(2-pyridylmethyl)thieno[3,2-d]pyrimidine-2-amine 46(A)

Ethyl 3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)propionate 47(E)

N-(2-dimethylaminoethyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 48(K)

3-(4-(2-furyl)thieno[3,2-d]pyrimidin-2-yl)propanol 49(M)

3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)propionicacid 50(N)

4-(2-furyl)-2-(3-oxo-3-(1-pyrrolidinyl)propyl)thieno[3,2-d]pyrimidine 51(J)

7-amino-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 52(C)

2-ethyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine 53(E)

4-(5-chloro-2-thienyl)-N,N-dimethylthieno[3,2-d]pyrimidine-2-amine 54(K)

2-(4-(2-furyl)thieno[3,2-d]pyrimidin-2-yl)ethanol 55(I)

N-2-dimethylamino-4-(2-furyl)thieno[3,2-d]pyrimidine-7-yl)-N′-phenylurea 56(G)

N-(2-dimethylamino-4-(2-furyl)thieno[3,2-d]pyrimidine-7-yl)acetamide 57(G)

N-(2-dimethylamino-4-(2-furyl)thieno[3,2-d]pyrimidine-7-yl)benzamide 58(E)

4-(2-furyl)-N-methylthieno[3,2-d]pyrimidine-2-amine 59(G)

N-(2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine-7-yl)methanesulphonamide 60(G)

N-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)-N-methyl-3-oxobutanamide 61(E)

4-(5-chloro-2-thienyl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine 62(C)

2-methyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine 63(C)

2-n-propyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine 64(C)

2-chloro-4-(2-thiazolyl)thieno[3,2-d]pyrimidine 65(E)

N,N-dimethyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 66(C)

4-(2-pyridyl)thieno[3,2-d]pyrimidine 67(E)

N-(2-hydroxyethyl)-4-(2-pyridyl)thieno[3,2-d]pyrimidine-2-amine 68(E)

N-(2-hydroxyethyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 69(L)

4-(2-furyl)-2-vinylthieno[3,2-d]pyrimidine 70(C)

2-isopropyl-4-(2-pyridyl)thieno[3,2-d]pyrimidine 71(E)

N-(2-methoxyethyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 72(E)

(2R)-7-bromo-4-(2-furyl)-2-(2-hydroxymethylpyrrolidin-1-yl)thieno[3,2-d]pyrimidine 73(A)

Ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-carboxylate 74(E)

tert-butyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 75(F)

N-(2-aminoethyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 76(E)

N,N-dimethyl-4-(4-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 77(H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)trifluoroacetamide 78(E)

N-(3,4-dimethoxybenzyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 79(F)

4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine 80(C)

2-ethyl-4-(4-methyl-2-thiazolyl)thieno [3,2-d]pyrimidine 81(K)

4-(2-furyl)thieno[3,2-d]pyrimidine-2-methanol 82(C)

2-ethyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine 83(H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)acetamide 84(H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)-3-methylbutanamide 85(H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)benzamide 86(H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)thiophene-2-carboxamide 87(H)

methyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 88(H)

isobutyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 89(H)

benzyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 90(H)

9-fluorenylmethyl (2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 91(I)

N-allyl-N′-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 92(I)

N-benzyl-N′-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 93(I)

N-cyclohexyl-N′-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 94(I)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)-N′-phenylurea 95(I)

N-(4-chlorophenyl)-N′-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 96(I)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)-N′-phenylthiourea 97(I)

N-(4-chlorophenyl)-N′-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)thiourea 98(H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)methanesulphonamide 99(H)

N-(2-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)-4-tert-butylphenylsulphonamide 100(A)

4-(2-furyl)-2-(2-pyridyl)thieno[3,2-d]pyrimidine 101(G)

N-(4-(2-furyl)thieno[3,2-d]pyrimidin-2-yl)acetamide 102(C)

2-chloro-4-(5-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine 103(C)

2-chloro-4-(4,5-dimethyl-2-thiazolyl)thieno[3,2-d]pyrimidine 104(E)

N,N-dimethyl-4-(5-methyl-2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 105(E)

N,N-dimethyl-4-(4,5-dimethyl-2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 106(C)

2-ethyl-4-(5-phenyl-2-oxazolyl)thieno[3,2-d]pyrimidine 107(D)

N,N-dimethyl-4-(1H-imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine 108(E)

N-(3,4-dimethoxybenzyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 109(C)

2-chloro-4-(5-methyl-2-pyridyl)thieno[3,2-d]pyrimidine 110(F)

4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 111(E)

(2R)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine 112(E)

N-allyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 113(C)

2-isopropyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine 114(C)

2-ethyl-4-(5-(4-methoxyphenyl)-2-oxazolyl)thieno[3,2-d]pyrimidine 115(E)

N,N-dimethyl-4-(5-methyl-2-pyridyl)thieno[3,2-d]pyrimidine-2-amine 116(G)

N-(4-(2-thiazolyl)thieno[3,2-d]pyrimidin-2-yl)acetamide 117(A)

4-(2-furyl)-2-(2-thienylmethyl)thieno[3,2-d]pyrimidine 118(A)

2-ethyl-4-(5-thiazolyl)thieno[3,2-d]pyrimidine 119(A)

2-ethyl-4-(2-ethylthieno[3,2-d]pyrimidin-4-yl)thieno[3,2-d]pyrimidine 120(D)

2-ethyl-4-(1H-triazol-3-yl)thieno[3,2-d]pyrimidine 121(D)

2-ethyl-4-(1H-imidazol-2-yl)thieno[3,2-d]pyrimidine 122(C)

4-(2-benzothiazolyl)-2-ethylthieno[3,2-d]pyrimidine 123(E)

tert-butyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 124(F)

N-(2-aminoethyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 125(H)

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)acetamide 126(I)

N-ethyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 127(I)

N-allyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 128(I)

N-cyclohexyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 129(H)

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)-3-methylbutanamide 130(H)

methyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 131(H)

isobutyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 132(I)

N-tert-butyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 133(I)

N-benzyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 134(I)

N-phenyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 135(I)

N-(4-chlorophenyl)-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea 136(I)

N-cyclohexyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)thiourea 137(I)

N-phenyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)thiourea 138(I)

N-(4-chlorophenyl)-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)thiourea 139(C)

2-tert-butyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine 140(C)

2-cyclopropyl-4-(2-thiazolyl)thieno[3,2-d]pyrimidine 141(C)

2-ethyl-4-(6-methyl-2-pyridyl)thieno[3,2-d]pyrimidine 142(H)

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)cyclohexylcarboxamide 143(H)

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)benzamide 144(H)

4-chloro-N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)benzamide 145(H)

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)thiophene-2-carboxamide 146(H)

phenyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 147(H)

benzyl (2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)carbamate 148(H)

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)methanesulphonamide 149(H)

N-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)butanesulphonamide 150(E)

(1RS)-N-(2-hydroxy-1-methylethyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 151(E)

N-(3-(1H-imidazol-1-yl)propyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-amine 152(E)

(2S)-2-(2-hydroxymethylpyrrolidin-1-yl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine 153(C)

4-(2-thiazolyl)-2-(2-thienyl)thieno[3,2-d]pyrimidine 154(C)

2-(2-chloroethyl)-4-(2-thiazolyl)thieno[3,2-d]pyrimidine 155(O)

4-(2-furyl)thieno[3,2-d]pyrimidine-2-carboxamide 156(B)

2-chloro-4-(3-thienyl)thieno[3,2-d]pyrimidine 157(E)

N,N-dimethyl-4-(3-thienyl)thieno[3,2]pyrimidine-2-amine 158(B)

2-chloro-4-phenylthieno[3,2-d]pyrimidine 159(E)

N,N-dimethyl-4-phenylthieno[3,2-d]pyrimidine-2-amine 160(B)

2-chloro-4-(3-furyl)thieno[3,2-d]pyrimidine 161(E)

N,N-dimethyl-4-(3-furyl)thieno[3,2-d]pyrimidine-2-amine 162(A)

2-chloro-4-(2-furyl)-6-nitrothieno[3,2-d]pyrimidine 163(A)

2-ethyl-4-(3-furyl)thieno[3,2-d]pyrimidine 164(B)

4-(3,5-dimethyl-4-isoxazolyl)-2-ethylthieno[3,2-d]pyrimidine 165(B)

2-chloro-4-(3-pyridyl)thieno[3,2-d]pyrimidine 166(E)

N,N-dimethyl-4-(3-pyridyl)thieno[3,2-d]pyrimidine-2-amine 167(C)

2-chloro-4-(1-methyl-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine 168(E)

N,N-dimethyl-4-(1-methyl-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine 169(E)

N,N-dimethyl-4-(3-hydroxymethyl-2-furyl)thieno[3,2-d]pyrimidine-2-amine 170(E)

N-(2-hydroxyethyl)-4-(1-methyl-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine 171(E)

N-2-hydroxyethyl)-4-(3-hydroxymethyl-2-furyl)thieno[3,2-d]pyrimidine-2-amine 172(C)

2-chloro-4-(1-ethyl-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine 173(E)

N,N-dimethyl-4-(1-ethyl-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine 174(E)

4-(1-ethyl-1H-imidazol-2-yl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine 175(C)

2-chloro-4-(1-(2-trimethylsilylethoxymethyl)-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine 176(E)

N,N-dimethyl-4-(1-(2-trimethylsilylethoxymethyl)-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine 177(C)

N,N-dimethyl-4-((1-ethoxycarbonylmethyl)-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine 178(K)

N,N-dimethyl-4-(1-(2-hydroxyethyl)-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine-2-amine 179(C)

2-ethyl-4-(1-methoxymethyl-1H-imidazol-2-yl)thieno[3,2-d]pyrimidine 180(C)

2-ethyl-4-(4-(2-trimethylsilylethoxymethyl)-4H-1,2,4-triazol-3-yl)thieno[3,2-d]pyrimidine 181(C)

2-chloro-4-(1-(2-trimethylsilylethoxymethyl)-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine 182(C)

2-chloro-4-(1-methyl-1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine 183(E)

N,N-dimethyl-4-(1-(2-trimethylsilylethoxymethyl)-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-2-amine 184(E)

N,N-dimethyl-4-(1-methyl-1H-pyrazol-5-yl)thieno[3,2-d]pyrimidine-2-amine 185(D)

N,N-dimethyl-4-(1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-2-amine 186(C)

N,N-dimethyl-4-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-d]pyrimidine-2-amine 187(C)

2-ethyl-4-(4-methyl-4H-1,2,4-triazol-3-yl)thieno[3,2-d]pyrimidine 188(A)

2-ethyl-4-(2-furyl)-6-methylthieno[3,2-d]pyrimidine

The general synthetic methods used for the preparation of these examples are set out below as Methods A to T.

Method A 2-Chloro-4-(2-furyl)thieno[3,2-d]pyrimidine (Example 3)

A solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in DMF (4 mL) was treated with PdCl₂(PPh₃)₂ (35 mg, 0.05 mmol) and 2-(tributylstannyl)-furan (315 μL, 1 mmol), stirred at room temperature for 16 h, the reaction mixture purified directly by chromatography (SiO₂: EtOAc:Heptane, 1:9) and the resulting cream solid recrystallised (EtOAc/Heptane) to give the title compound (122 mg, 52%) as a cream solid.

Method B 2-Chloro-4-(5-chloro-2-thienyl)thieno[3,2-d]pyrimidine

A solution of Pd(OAc)₂ (12 mg, 5 mmol %) and PPh₃ (52 mg, 20 mol %) in THF (2 mL) was stirred for 5 min, treated dropwise with a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in THF (1 mL), stirred for 5 min, treated with 5-chlorothiophene-2-boronic acid (244 mg, 1.5 mmol) then saturated aqueous NaHCO₃ (1 mL) refluxed for 4 h, cooled, diluted with H₂O and filtered to give the title compound (268 mg, 94%) as a grey solid; NMR δ_(H) (400 MHz, CDCl₃) 7.10 (1H, d, J 4.0 Hz), 7.55 (1H, d, J 5.5 Hz), 7.85 (1H, d, J 4.5 Hz) and 8.08 (1H, d, J 5.5 Hz)

Method C 2-Chloro-4-(2-thiazolyl)thieno[3,2-d]pyrimidine (Example 64)

A stirred solution of thiazole (0.14 mL, 2 mmol) in dry THF (10 mL) at −78° C., under argon was treated with n-BuLi (1.6-M in hexanes, 1.3 mL, 2 mmol), stirred for 30 min, treated with a solution of ZnCl₂ (1.0-M in Et₂O, 2.0 mL, 2 mmol) and allowed to warm gradually to room temperature. The mixture was treated with a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in THF (5 mL) then Pd(PPh₃)₄ (100 mg, 10 mol %) refluxed for 17 h, cooled, diluted with saturated NH₄Cl solution and extracted with EtOAc. The organic extracts were dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; isohexane:CH₂Cl₂ (2:1)] to give the title compound (75 mg, 26%) as a white solid.

Method D 2-Ethyl-4-(1H-imidazol-2-yl)thieno[3,2-d]pyrimidine (Example 121)

A stirred solution of 1-(2-trimethylsilyl)ethoxymethyl-1H-imidazole (295 mg, 1.5 mmol) in dry THF (10 mL) at −78° C., under argon was treated with n-BuLi (1.6-M in hexanes, 0.93 mL, 1.5 mmol), stirred for 30 min, treated with a solution of ZnCl₂ (1.0-M in Et₂₀, 1.5. mL, 1.5 mmol) and the mixture allowed to warm gradually to room temperature. The mixture was treated with 4-chloro-2-ethylthieno[3,2-d]pyrimidine (148 mg, 0.75 mmol) and Pd(PPh₃)₄ (100 mg), refluxed for 3 h, cooled, diluted with saturated NH₄Cl solution, extracted with EtOAc, dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; heptane:EtOAc (7:1) then (4:1)] to give the intermediate coupled product as a viscous oil (140 mg). A portion of this material (130 mg, 0.36 mmol) was dissolved in THF (5 mL), treated with a solution of tetra-n-butylammonium fluoride (1-M in THF, 0.72 mL, 0.72 mmol), refluxed for 4 hr, cooled, extracted with EtOAc, dried (MgSO₄) concentrated in vacuo and purified by chromatography [SiO₂; heptane:EtOAc (4:1) then (2:1)] to give the title compound (62 mg, 39%) as a white solid.

Method E 7-Bromo-4-(2-furyl)-N-(2-hydroxyethyl)thieno[3,2-d]pyrimidine-2-amine (Example 15

A solution of 7-bromo-2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine (110 mg, 0.35 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was treated with ethanolamine (32 μL, 0.52 mmol), heated at 90° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂: EtOAc: Heptane, 1:1) to give the title compound (45 mg, 38%) as a yellow solid.

Method F 4-(2-Furyl)thieno[3,2-d]pyrimidine-2-amine (Example 79)

A solution of N-(3,4-dimethoxybenzyl)-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (199 mg, 0.54 mmol) in TFA (1 mL) was heated at 60° C. for 1 h, cooled, poured into sat. NaHCO₃, extracted with EtOAc, dried (MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂:EtOAc:Heptane, 1:1 and MeOH:DCM, 1:19) to give the title compound (108 mg, 92%) as a cream solid.

Method G N-(4-(2-Furyl)thieno[3,2-d]pyrimidin-2-yl)acetamide (Example 101)

An ice-cold solution of 4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (130 mg, 0.6 mmol) in pyridine (1 mL) was treated with acetyl chloride (47 μL, 0.66 mmol), stirred at room temperature for 16 h, poured into water, extracted with EtOAc, dried (MgSO₄) and concentrated in vacuo and purified by chromatography (SiO₂:EtOAc:Heptane, 1:1) to give the title compound (125 mg, 80%) as a cream solid.

Method H N-(2-(4-(2-Thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)acetamide (Example 125)

A solution of N-(2-aminoethyl)-4-(2-thiazolyl))thieno[3,2-d]pyrimidine-2-amine (0.040 g, 0.14 mmol) in DMF (2 mL) was treated with triethylammonium methylpolystyrene carbonate (0.066 g, 0.22 mmol) followed by acetyl chloride (0.023 g, 0.29 mmol), shaken at room temperature for 7 h, treated with tris-(2-aminoethyl)amine polystyrene (0.19 g, 0.87 mmol), shaken at room temperature for 16 h, treated with polystyrene 4-benzyloxybenzaldehyde (0.19 g, 0.28 mmol), shaken for a further 3 h, filtered and concentrated in vacuo to give the title compound as a yellow solid.

Method I N-Ethyl-N′-(2-(4-(2-thiazolyl)thieno[3,2-d]pyrimidine-2-ylamino)ethyl)urea (Example 126)

A solution of N-(2-aminoethyl)-4-(2-thiazolyl))thieno[3,2-d]pyrimidine-2-amine (0.040 g, 0.14 mmol) in anhydrous DMF (2 mL) was treated with ethyl isocyanate (0.015 g, 0.22 mmol), shaken at 35° C. for 1 h, treated with tris-(2-aminoethyl)amine polystyrene (0.19 g, 0.88 mmol), shaken at 35° C. for 4 h, filtered and concentrated in vacuo to give the title compound as a yellow solid.

Method J 7-Amino-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (Example 51)

A solution of N,N-dimethyl-4-(2-furyl)-7-nitrothieno[3,2-d]pyrimidine (85 mg, 0.29 mmol) in MeOH (4 mL), under argon, was treated with a catalytic amount of Pd on carbon (10%), hydrogenated at room temperature for 1 h, filtered through celite, concentrated in vacuo and purified by chromatography (SiO₂:EtOAc:Heptane, 1:4) to give the title compound (62 mg, 82%) as a brown solid.

Method K 2-(4-(2-Furyl)thieno[3,2-d]pyrimidin-2-yl)ethanol (Example 54)

A solution of ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-acetate (0.10 g, 0.35 mmol) in dichloromethane (13 mL) at −75° C. was treated dropwise with di-iso-butylaluminium hydride (0.87 mL, 1.0-M), stirred for 17 h, warmed to ambient temperature and partitioned between Rochelle's salt and dichloromethane. The combined organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂:EtOAc) to give the title compound (21 mg, 25%) as a white solid.

Method L 4-(2-Furyl)-2-vinylthieno[3,2-d]pyrimidine (Example 69)

A solution of 2-(4-(2-furyl)thieno[3,2-d]pyrimidin-2-yl)ethanol (0.15 g, 0.61 mmol) in THF (5 mL) at 0° C. was treated with diisopropylethylamine (0.095 g, 0.73 mmol) then methanesulfonyl chloride (0.72 g, 0.67 mmol), warmed to room temperature over 16 h, partitioned between ethyl acetate and water, the organic phase dried (MgSO₄) and concentrated in vacuo to give the intermediate mesylate (0.10 g, 50%) as a white solid. A sample of this compound (59 mg, 0.18 mmol) was dissolved in CH₂Cl₂, treated with DBU (0.042 g, 0.27 mmol), stirred at room temperature for 18 h, partitioned between ethyl acetate and water and the organic phase was dried (MgSO₄) and concentrated in vacuo to give the title compound (22 mg, 50%) as a white solid.

Method M 3-(4-(2-Furyl)thieno[3,2-d]pyrimidine-2-yl)propionic acid (Example 49)

A solution of ethyl 3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)propionate (0.07 g, 0.23 mmol) in THF (1.0 mL) and water (1.0 mL) was treated with lithium hydroxide (0.10 g, 2.32 mmol), stirred at room temperature for 16 h, concentrated in vacuo, dissolved in water, acidified to pH 2 by the addition of HCl (0.1 mL, 6.0-M), cooled in ice and filtered to give the title compound (0.052 g, 81%) as a white solid.

Method N 4-(2-Furyl)-2-(3-oxo-3-(1-pyrrolidinyl)propyl)thieno[3,2-d]pyrimidine (Example 50)

A mixture of trimethylaluminium in toluene (1.3 mL, 2.0-M) and pyrrolidine (0.22 mL, 2.65 mmol) in toluene was heated at 80° C. for 0.5 h, treated with a solution of ethyl 3-(4-(2-furyl)thieno[3,2-d]pyrimidine-2-yl)propionate (0.1 g, 0.33 mmol) in toluene (2.0 mL), stirred at 80° C. for 17 h, cooled to room temperature and partitioned between sat. aq. NH₄Cl and ethyl acetate. The combined organic phase was dried MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂:EtOAc-methanol, 9:1) to give the title compound (27 mg, 25%).

Method O 4-(2-Furyl)thieno[3,2-d]pyrimidine-2-carboxamide (Example 155)

Ammonia gas was bubbled through a hot solution of ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-carboxylate (0.156 g, 0.57 mmol) in ethanol (20 mL) for 3 h then the mixture cooled and the resulting white solid filtered to give the title compound (94 mg, 67%) as a white solid.

Method P 4,7-Bis(2-furyl)-N,N-dimethylthieno[3,2-d]pyrimidine-2-amine (Example 31)

A mixture of AsPh₃ (73 mg, 0.24 mmol) in DMF (2 mL) was treated with Pd(OAc)₄ (13 mg, 0.06 mmol), stirred at room temperature for 10 min, treated with 7-bromo-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (194 mg, 0.6 mmol) and 2-(tributylstannyl)-furan (340 μL, 1.1 mmol), heated to 100° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂:EtOAc:Heptane, 1:9) to give the title compound (27 mg, 15%) as a orange solid.

Method Q 2-Isopropylthieno[3,2-d]pyrimidine-4-ol

A mixture of 3-aminothiophene-2-carboxamide (2.0 g, 14.1 mmol) and triethylamine (1.71 g, 16.9 mmol) in toluene (20 mL) at room temperature was treated with 2-methylpropionic anhydride (2.45 g, 15.5 mmol), refluxed for 4 h, cooled, poured into saturated NaHCO₃ (100 mL) and extracted with ethyl acetate (4×50 mL). The combined organic phase was washed with brine(2×50 mL), dried (Na₂SO₄) and concentrated in vacuo to the intermediate N-acylated compound (2.90 g, 99%) as a pale yellow solid. A sample of this compound (2.85 g, 13.44 mmol) was dissolved in NaOH (34 mL, 1.0-M), refluxed for 1 h, cooled, acidified to pH 2 by addition of HCl (7.0 mL, 6.0-M), filtered and dried to give the title compound (2.30 g, 88%) as a white solid: IR ν_(max) (Nujol)/cm⁻¹ 2956, 2925, 1676, 1599, 1464, 780; NMR δ_(H) (400 MHz, DMSO) 1.20 (6H, d J 6.5 Hz), 2.90 (1H, heptet, J 6.5 Hz), 7.40 (1H, d J 5.0 Hz), 8.15 (1H, d, J 5.0 Hz) and 12.30 (1H, br).

Method R 2-Cyclopropylthieno[3,2-d]pyrimidine-4-ol

Dry HCl gas was bubbled through a solution of methyl 3-aminothiophene-2-carboxylate (1.64 g, 10.4 mmol) and cyclopropanecarbonitrile (27 mL) in dioxane (40 mL) for 1 h then the reaction mixture was diluted with cold water (2 volumes), basified with NH₄OH (50 mL) and the resulting solid filtered and air dried to give the title compound (1.44 g, 72%) as a white solid: IR ν_(max) (Nujol)/cm⁻¹ 2925, 1664, 1597, 788; NMR δ_(H) (400 MHz, DMSO) 1.04 (4H, m), 2.00 (1H, m), 7.20 (1H, d J 5.0 Hz), 8.10 (1H, d, J 5.0 Hz) and 12.60 (1H, br).

Method S 4-Chloro-2-isopropylthieno[3,2-d]pyrimidine

A suspension of 2-isopropylthieno[3,2-d]pyrimidine-4-ol (1.66 g, 8.56 mmol) in POCl₃ (30 mL) was refluxed for 1 h, cooled, diluted with chloroform (100 mL) and poured into a mixture of ice and NH₄OH (150 mL). The organic phase was separated, washed with saturated NaHCO₃ (20 mL), water and brine, dried (MgSO₄) and concentrated in vacuo to give the title compound (2.01 g, 99%) as a pale yellow solid: IR ν_(max) (Nujol)/cm⁻¹ 3065, 2960, 2926, 2855, 1561, 1513, 1457, 803; NMR δ_(H) (400 MHz, CDCl₃) 1.40 (6H, d J 6.5 Hz), 3.38 (1H, heptet, J 6.5 Hz), 7.60 (1H, d J 5.0 Hz), 8.05 (1H, d, J 5.0 Hz).

Method T Ethyl 4-hydroxythieno[3,2-d]pyrimidine-2-carboxylate

A mixture of 3-aminothiophene-2-carboxamide (1.23 g, 8.65 mmol) and EtOH (25 mL) was treated with NaOEt (1.2 g, 17.3 mmol) and diethyloxalate (2.3 mL, 17.3 mmol), refluxed for 18 h, cooled, concentrated in vacuo, treated with water, acidified with HOAc and filtered to give the title compound (1.43 g, 74%) as a cream solid: IR v_(max) Nujol)/cm⁻¹ 3180, 3119, 3078, 3006, 2955, 2924, 2854, 1737, 1667, 1651, 1300 and 1176; NMR δ_(H) (400 MHz, DMSO) 1.37 (3H, t, J 7.0 Hz), 4.40 (2H, q, J 7.0 Hz), 7.58 (1H, d, J 5.0 Hz), 8.30 (1H, d, J 5.1 Hz), and 12.92 (1H, s).

TABLE 2 Analytical data HPLC is carried out using the following conditions: Column. Supelcosil ABZ⁺ (170 × 4.6 mm), particle size 5 μM, mobile phase MeOH: 10 mM aq NH₄OAc (80:20), (70:30) or (60:40) (specified in Table 2), flow rate 1.0 mL/min., detection wavelength λ = 230 nM (unless otherwise stated), retention times are provided in Table 2. Example Yield(%) Physical Data 1 61 Mp 135.6-135.8° C.; IR ν_(max) (Nujol)/cm⁻¹ 3111, 3082, 3072, 1529, 1467, 1425, 1254, 1238 and 1205; NMR δ_(H) (400 MHz, CDCl₃) 7.28 (1H, dd, J 5.0, 4.0 Hz), 7.54 (1H, d, J 5.5 Hz), 7.69 (1H, dd, J 5.0, 1.0 Hz), 8.07 (1H, d, J 5.5 Hz), 8.08 (1H, dd, J 4.0, 1.0 Hz); Anal. Calcd for C₁₀H₅ClN₂S₂: C, 47.52; H, 1.99, N, 11.08. Found: C, 47.54; H, 2.00; N, 10.93; M/Z 253 (M + H)⁺. 2 98 mp 139.2-140.0° C.; IR ν_(max) (Nujol)/cm⁻¹ 1551, 1517, 1466, 1393, 1361, 793 and 707; NMR δ_(H) (400 MHz, CDCl₃) 3.30 (6H, s), 7.22 (1H, dd, J 5.0, 4.0 Hz), 7.27 (1H, d, J 5.5 Hz), 7.54 (1H, dd, J 5.5, 1.0 Hz), 7.79 (1H, d, J 5.5 Hz), 7.95 (1H, dd, J 3.5, 1.0 Hz); Anal. Calcd for C₁₂H₁₁N₃S₂: C, 55.15; H, 4.24, N, 16.07. Found: C, 55.05; H, 4.12; N, 15.88. 3 52 mp 146.9-147.6° C.; IR ν_(max) (Nujol)/cm⁻¹ 3132, 3105, 3064, 1594, 1522, 1463 and 1264; NMR δ_(H) (400 MHz, CDCl₃) 6.69-6.72 (1H, m), 5.50 (1H, d, J 5.5 Hz), 7.60 (1H, dd, J 3.5, 1.0 Hz), 7.80 (1H, d, J 1.0 Hz), 8.10 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₀H₅ClN₂OS + 0.4 H₂O: C, 49.25; H, 2.40, N, 11.49. Found: C, 48.87; H, 2.04; N, 11.65. 4 78 mp 128.5-128.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3314, 3065, 1542, 1498, 1466 and 1363; NMR δ_(H) (400 MHz, CDCl₃) 1.71-1.81 (1H, m), 1.88-2.08 (2H, m), 2.13-2.23 (1H, m), 3.68-3.79 (3H, m), 3.82-3.98 (2H, m), 4.40 (1H, s), 7.21-7.27 (2H, m), 7.56 (1H, dd, J 5.0, 1.0 Hz), 7.83 (1H, d, J 5.5 Hz), 7.98 (1H, dd, J 4.0, 1.0 Hz); Anal. Calcd for C₁₅H₁₅N₃OS₂: C, 56.76; H, 4.76, N, 13.23. Found: C, 56.72; H, 4.80; N, 13.14. 5 77 mp 129.3-130.4° C.; IR ν_(max) (Nujol)/cm⁻¹ 3125, 3095, 3066, 1601, 1554, 1462, 1403 and 792; NMR δ_(H) (400 MHz, CDCl₃) 3.29 (6H, s), 6.60-6.64 (1H, m), 7.23 (1H, d, J 5.5 Hz), 7.38 (1H, d, J 3.5 Hz), 7.70-7.72 (1H, m), 7.80-7.84 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₂H₁₁N₃OS: C, 58.76; H, 4.52, N, 17.12. Found: C, 58.89; H, 4.52; N, 16.89. 6 75 mp dec. >230° C.; IR ν_(max) (Nujol)/cm⁻¹ 3426, 3160, 3075, 1616, 1573, 1523 and 1447; NMR δ_(H) (400 MHz, DMSO) 2.13-2.22 (2H, m), 3.45 (2H, t, J 6.5 Hz), 4.33 (2H, t, J 7.0 Hz), 4.49-4.87 (1H, s), 7.36-7.39 (1H, m), 7.43-7.46 (1H, m), 7.69-7.72 (1H, m), 7.84-7.87 (1H, m), 8.00 (1H, d, J 4.5 Hz), 8.04 (1H, d, J 4.0 Hz), 8.42 (1H, d, J 5.5 Hz), 9.23 (1H, s); Anal. Calcd for C₁₆H₁₅N₅S₂ + 2HCl + 0.25 H₂O: C, 44.44, H, 4.43, N, 16.20. Found: C, 44.09; H, 4.34; N, 16.14. 7 61 mp 110.6-111.8° C.; IR ν_(max) (Nujol)/cm⁻¹ 3266, 1590, 1553, 1516, 1461 and 791; NMR δ_(H) (400 MHz, CDCl₃) 3.67-3.73 (2H, m), 3.89-3.93 (2H, m), 3.93-4.08 (1H, s), 5.56 (1H, t, J 5.0 Hz), 7.21-7.25 (2H, m), 7.56 (1H, dd, J 5.0, 1.0 Hz), 7.83 (1H, d, J 5.5 Hz), 7.97 (1H, dd, J 3.5, 1.0 Hz); Anal. Calcd for C₁₂H₁₁N₃OS₂: C, 51.97, H, 4.00, N, 15.14. Found: C, 51.75; H, 3.96; N, 15.11. 8 95 mp 114.6-115.1° C.; IR ν_(max) (Nujol)/cm⁻¹ 3412, 3059, 1549, 1481, 1464, 1341, 1327 and 725; NMR δ_(H) (400 MHz, CDCl₃) 4.13 (3H, s), 7.24-7.27 (1H, m), 7.42 (1H, d, J 5.5 Hz), 7.62 (1H, dd, J 5.0, 1.0 Hz), 7.96 (1H, d, J 5.5 Hz), 8.04 (1H, dd, J 3.5, 1.0 Hz); Anal. Calcd for C₁₁H₈N₂OS₂: C, 53.21, H, 3.25, N, 11.28. Found: C, 53.21; H, 3.27; N, 11.24. 9 36 IR ν_(max) (Nujol)/cm⁻¹ 3065, 2925, 2855, 1539, 1464, 1352, 716; NMR δ_(H) (400 MHz, CDCl₃) 1.50 (3H, t J 7.5 Hz), 3.10 (2H, q, J 7.5 Hz), 7.26 (1H, m), 7.54 (1H, d, J 5.5 Hz), 7.61 (1H, dd, J 1.0, 5.0 Hz), 7.96 (1H, d, J 5.5 Hz), 8.04 (1H, dd, J 1.0, 3.8 Hz). 10 57 mp dec. >235° C.; IR ν_(max) (Nujol)/cm⁻¹ 3417, 3105, 2623, 1654, 1633, 1508 and 1466; NMR δ_(H) (400 MHz, DMSO) 2.13-2.22 (2H, m), 3.49 (2H, t, J 6.5 Hz), 4.33 (2H, t, J 7.0 Hz), 4.02-4.66 (2H, s), 6.88-6.90 (1H, m), 7.45 (1H, s), 7.51 (1H, s), 7.70 (1H, t, J 1.7 Hz), 7.85 (1H, t, J 1.7 Hz), 8.23 (1H, s), 8.45 (1H, d, J 5.0 Hz), 9.22 (1H, s), 14.59-14.87 (1H, s); Anal. Calcd for C₁₆H₁₅N₅OS + 2HCl + 1.5 H₂O: C, 45.18, H, 4.74, N, 16.47, Cl, 16.67. Found: C, 45.40; H, 4.39; N, 16.59, Cl, 16.42. 11 82 mp 147.6-148.8° C.;; IR ν_(max) (Nujol)/cm⁻¹ 3141, 3112, 3074, 1594, 1536, 1524, 1487, 1471, 1239, 1192, 1167, 1131 and 810; NMR δ_(H) (400 MHz, CDCl₃) 6.71-6.73 (1H, m), 7.66 (1H, dd, J 3.5, 1.0 Hz), 7.69 (1H, d, J 5.5 Hz), 7.81-7.83 (1H, m), 8.19 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₁H₅F₃N₂OS: C, 48.89, H, 1.86, N, 10.36. Found: C, 48.67; H, 1.92; N, 10.25. 12 78 mp 164.4-164.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3153, 3121, 1596, 1498, 1466, 1272 and 804; NMR δ_(H) (400 MHz, CDCl₃) 2.51 (3H, s), 6.68-6.70 (1H, m), 7.57 (1H, dd, J 3.5, 1.0 Hz), 7.72 (1H, dd, J 2.5, 1.0 Hz), 7.78-7.79 (1H, m); Anal. Calcd for C₁₁H₇ClN₂OS: C, 52.70, H, 2.82, N, 11.17. Found: C, 52.91; H, 2.82; N, 11.05. 13 34 mp dec. 213.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3142, 3113, 3898, 3070, 1594, 1515, 1460, 1271 and 765; NMR δ_(H) (400 MHz, DMSO) 6.90-6.93 (1H, m), 7.68 (1H, d, J 3.5 Hz), 8.27 (1H, s), 8.83 (1H, s); Anal. Calcd for C₁₀H₄BrClN₂OS: C, 38.06, H, 1.28, N, 8.87. Found: C, 38.22; H, 1.38; N, 8.74. 14 75 mp 107.9-108.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3279, 1607, 1572, 1460, 1377, 1067 and 791; NMR δ_(H) (400 MHz, CDCl₃) 3.66-3.72 (2H, m), 3.88-3.93 (2H, m), 4.33-4.60 (1H, s), 5.56 (1H, t, J 5.0 Hz), 6.62-6.65 (1H, m), 7.21 (1H, d, J 5.5 Hz), 7.38 (1H, d, J 3.5 Hz), 7.73 (1H, s), 7.88 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₂H₁₁N₃O₂S: C, 55.16, H, 4.24, N, 16.07. Found: C, 55.16; H, 4.23; N, 15.97. 15 38 mp 173.4-174.4° C.; IR ν_(max) (Nujol)/cm⁻¹ 3394, 3260, 3110, 3083, 1600, 1555, 1463 and 1439; NMR δ_(H) (400 MHz, CDCl₃) 3.70-3.72 (2H, m), 3.89-3.95 (2H, m), 4.47-4.67 (1H, s), 5.67-5.74 (1H, m), 6.64-6.67 (1H, m), 7.40 (1H, d, J 3.5 Hz), 7.74 (1H, s), 7.87 (1H, s); Anal. Calcd for C₁₂H₁₀BrN₃O₂S + 0.25 H₂O: C, 41.27; H, 3.18, N, 12.03. Found: C, 41.28; H, 3.04; N, 12.04. 16 75 mp 149.9-150.6° C.; IR ν_(max) (Nujol)/cm⁻¹ 3404, 3219, 1602, 1550, 1507, 1464 and 1440; NMR δ_(H) (400 MHz, CDCl₃) 2.38 (3H, s), 3.67-3.73 (2H, m), 3.88-3.94 (2H, m), 5.13 (1H, s), 5.57 (1H, t, J 5.0 Hz), 6.62-6.64 (1H, m), 7.37 (1H, dd, J 3.5, 1.0 Hz), 7.51 (1H, d, J 1.0 Hz), 7.72-7.73 (1H, m); Anal. Calcd for C₁₃H₁₃N₃O₂S: C, 56.71; H, 4.76, N, 15.25. Found: C, 56.67; H, 4.79; N, 15.19. 17 64 mp 231.0-231.6° C.; IR ν_(max) (Nujol)/cm⁻¹ 3109, 3094, 1531, 1469, 1232 and 790; NMR δ_(H) (400 MHz, DMSO) 7.48-7.58 (2H, m), 7.72 (1H, d, J 5.5 Hz), 8.10-8.17 (2H, m), 8.52 (1H, s), 8.75 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₄H₇ClN₂S₂: C, 55.33; H, 2.33, N, 9.25. Found: C, 55.22; H, 2.32; N, 9.41. 18 56 IR ν_(max) (Nujol)/cm⁻¹ 3096, 2924, 1595, 1528, 1488, 1463, 1303, 1016, 808 and 768; NMR δ_(H) (400 MHz, DMSO) 1.36 (3H, t, J 7.7 Hz), 3.00 (2H, q, J 7.7 Hz), 6.85 (1H, dd, J 1.8, 3.5 Hz), 7.54 (1H, dd, J 0.8, 3.5 Hz), 7.58 (1H, d, J 5.5 Hz), 8.17 (1H, dd, J 0.8, 1.8 Hz), 8.49 (1H, d, J 5.5 Hz). 19 89 mp 166.5-167.3° C.; IR ν_(max) (Nujol)/cm⁻¹ 3094, 3053, 1556, 1463, 1407, 1354 and 793; NMR δ_(H) (400 MHz, CDCl₃) 3.33 (6H, s), 7.29 (1H, d, J 5.5 Hz), 7.37-7.43 (2H, m), 7.82 (1H, d, J 5.5 Hz), 7.87-7.92 (2H, m), 8.16 (1H, s); Anal. Calcd for C₁₆H₁₃N₃S₂: C, 61.71; H, 4.21, N, 13.49. Found: C, 61.82; H, 4.26; N, 13.52. 20 64 mp 173.4-174.4° C.; IR ν_(max) (Nujol)/cm⁻¹ 3409, 3260, 3126, 3094, 1587, 1545 and 1339; NMR δ_(H) (400 MHz, CDCl₃) 3.70-3.77 (2H, m), 3.90-3.97 (2H, m), 5.60 (1H, t, J 5.0 Hz), 7.27 (1H, d, J 5.5 Hz), 7.39-7.46 (2H, m), 7.86-7.93 (3H, m), 8.19 (1H, s); Anal. Calcd for C₁₆H₁₃N₃OS₂ + 0.25 H₂O: C, 57.93; H, 4.10, N, 12.66. Found: C, 57.78; H, 3.96; N, 12.76. 21 42 mp 112.3-122.7° C.; NMR δ_(H) (400 MHz, CDCl₃) 1.30 (3H, t, J 7.3 Hz), 3.54-3.62 (2H, m), 5.06 (1H, s), 7.26 (1H, d, J 5.5 Hz), 7.45-7.48 (1H, m), 7.81 (1H, d, J 5.5 Hz), 7.90 (1H, dd, J 5.0 Hz), 8.20-8.23 (1H, m); Anal. Calcd for C₁₂H₁₁N₃S₂: C, 55.15; H, 4.24, N, 16.07. Found: C, 55.13; H, 4.29; N, 15.90. 22 63 mp 118.7-119.5° C.; IR ν_(max) (Nujol)/cm⁻¹ 3094, 1602, 1552, 1464 and 1377; NMR δ_(H) (400 MHz, CDCl₃) 3.33 (6H, s), 6.61-6.64 (1H, m), 7.40 (1H, d, J 3.5 Hz), 7.71-7.72 (1H, m), 7.81 (1H, s); Anal. Calcd for C₁₂H₁₀BrN₃OS: C, 44.46; H, 3.11, N, 12.96. Found: C, 44.24; H, 3.06; N, 13.01. 23 90 mp 113.1-113.7° C.; IR ν_(max) (Nujol)/cm⁻¹ 3115, 1602, 1560, 1548, 1508, 1466 and 1409; NMR δ_(H) (400 MHz, CDCl₃) 2.38 (3H, s), 3.31 (6H, s), 6.58-6.62 (1H, m), 7.36 (1H, d, J 3.5 Hz), 7.44-7.45 (1H, m), 7.69-7.70 (1H, m); Anal. Calcd for C₁₆H₁₃N₃OS + 0.15 H₂O: C, 59.59; H, 5.12, N, 16.04. Found: C, 59.83; H, 2.89; N, 15.70. 24 31 mp 209.2-209.5° C.; IR ν_(max) (Nujol)/cm⁻¹ 1531, 1523, 1463, 1377, 1247 and 781; NMR δ_(H) (400 MHz, CDCl₃) 7.47 (1H, m), 7.54 (1H, d, J 6.0 Hz), 7.95 (1H, dt, J 8.0, 2.0 Hz), 8.19 (1H, d, J 5.5 Hz), 8.73-8.77 (1H, m), 8.84-8.87 (1H, m); Anal. Calcd for C₁₁H₆ClN₃S + 0.1 H₂O: C, 52.56; H, 2.45, N, 16.72. Found: C, 52.69; H, 2.41; N, 16.64. 25 IR ν_(max) (Nujol)/cm⁻¹ 2955, 2924, 2854, 1600, 1555, 1526, 1490, 1456, 1378 and 1270; NMR δ_(H) (400 MHz, DMSO) 8.18 (1H, m) 7.97 (1H, s), 7.35 (1H, m), 7.14 (1H, m), 6.67 (1H, m), 3.68-3.58 (4H, m), 3.58-3.48 (4H, m). 26 IR ν_(max) (Nujol)/cm⁻¹ 3261, 2924, 2854, 1604, 1573, 1547, 1513, 1455, 1443 and 1330; NMR δ_(H) (400 MHz, CDCl₃) 7.86 (1H, d, J 5.5 Hz), 7.72 (1H, s), 7.48-7.23 (7H, m), 6.62 (1H, dd, J 4.0, 1.5 Hz), 5.53 (1H, br s), 4.76 (2H, d, J 5.9 Hz). 27 13 mp 186.6-188.0° C.; IR ν_(max) (Nujol)/cm⁻¹ 3053, 1556, 1466, 1359 and 786; NMR δ_(H) (400 MHz, CDCl₃) 3.37 (6H, s), 7.27-7.33 (1H, m), 7.39-7.45 (1H, m), 7.86-7.95 (2H, m), 8.66 (1H, d, J 8.0 Hz), 8.81-8.84 (1H, m). 28 40 mp 197.1-197.7° C.; IR ν_(max) (Nujol)/cm⁻¹ 3406, 3103, 3084, 1569, 1520 and 1464; NMR δ_(H) (400 MHz, CDCl₃) 6.49-6.50 (1H, m), 7.14 (1H, dt, J 3.0, 1.0 Hz), 7.20-7.23 (1H, m), 7.48 (1H, d, J 5.5 Hz), 8.01 (1H, d, J 5.5 Hz), 9.88-10.01 (1H, s); Anal. Calcd for C₁₀H₆ClN₃S: C, 50.96; H, 2.57, N, 17.82. Found: C, 50.87; H, 2.54; N, 17.64. 29 31 IR ν_(max) (Nujol)/cm⁻¹ 2924, 2854, 1739, 1727, 1598, 1532, 1467, 1369, 1348 and 1191; NMR δ_(H) (400 MHz, CDCl₃) 8.05 (1H, m), 7.78 (1H, m), 7.60 (1H, m), 7.49 (1H, m), 6.42 (1H, m), 4.20 (2H, q, J 7.0 Hz), 4.18 (2H, s) and 1.22 (3H, t, J 7.0 Hz); M/Z 289 (M + H)⁺. 30 67 mp 183.2-183.8° C.; IR ν_(max) (Nujol)/cm⁻¹ 3071, 1536, 1522, 1465 and 1252; NMR δ_(H) (400 MHz, CDCl₃) 7.58 (1H, d, J 5.5 Hz), 8.23 (1H, d, J 5.5 Hz), 8.79-8.83 (2H, m), 9.95 (1H, d, J 1.5 Hz); Anal. Calcd for C₁₀H₅ClN₄S: C, 48.30; H, 2.03, N, 22.52. Found: C, 48.28; H, 2.10; N, 22.40. 31 15 IR ν_(max) (Nujol)/cm⁻¹ 2726, 1561, 1509, 1461 and 1377; NMR δ_(H) (400 MHz, CDCl₃) 3.35 (6H, s), 6.54-6.55 (1H, m), 6.62-6.64 (1H, m), 7.41 (1H, dd, J 3.5, 1.0 Hz), 7.45 (1H, d, J 3.5 Hz), 7.48-7.49 (1H, m), 7.72-7.73 (1H, m), 8.05 (1H, s); Anal. Calcd for C₁₆H₁₃N₃O₂S + 0.3 H₂O: C, 60.67; H, 4.33, N, 13.27. Found: C, 60.49; H, 4.09; N, 13.33. 32 94 mp 247.4-248.6° C.; IR ν_(max) (Nujol)/cm⁻¹ 3080, 3072, 1568, 1544, 1462 and 1402; NMR δ_(H) (400 MHz, CDCl₃) 3.29 (6H, s), 6.41-6.44 (1H, m), 7.04-7.06 (1H, m), 7.09-7.12 (1H, m), 7.23 (1H, d, J 5.5 Hz), 7.76 (1H, d, J 5.0 Hz), 9.74-9.83 (1H, s); Anal. Calcd for C₁₂H₁₂N₄S + 0.2 H₂O: C, 58.14; H, 5.04, N, 22.60. Found: C, 58.16; H, 4.84; N, 22.64. 33 100 mp 173.9-174.3° C.; IR ν_(max) (Nujol)/cm⁻¹ 1586, 1558, 1531, 1462, 1352 and 793; NMR δ_(H) (400 MHz, CDCl₃) 3.36 (6H, s), 7.29 (1H, d, J 5.5 Hz), 7.92 (1H, d, J 5.5 Hz), 8.70 (1H, d, J 2.5 Hz), 8.76-8.78 (1H, m), 8.76-8.78 (1H, m), 9.87 (1H, d, J 1.5 Hz); Anal. Calcd for C₁₂H₁₁N₅S + 0.1 H₂O: C, 55.62; H, 4.36, N, 27.03. Found: C, 55.46; H, 4.25; N, 26.83. 34 55 mp 191.5-192.4° C.; IR ν_(max) (Nujol)/cm⁻¹ 3298, 3082, 3060, 1589, 1567, 1533, 1465, 1344, 1062 and 797; NMR δ_(H) (400 MHz, DMSO) 3.47-3.56 (2H, m), 3.57-3.65 (2H, m), 4.73 (1H, s), 7.19 (1H, s), 7.28 (1H, d, J 5.0 Hz), 8.31 (1H, d, J 5.5 Hz), 8.86 (1H, d, J 2.5 Hz), 8.91 (1H, dd, J 2.5, 1.5 Hz), 9.72 (1H, s). 35 IR ν_(max) (Nujol)/cm⁻¹ 3140, 3089, 2925, 2854, 1601, 1552, 1527, 1519, 1493, 1455 and 1265; NMR δ_(H) (400 MHz, CDCl₃) 7.85 (1H, d, J 5.5 Hz), 7.72 (1H, s), 7.38 (1H, m), 7.22 (1H, d, J 5.5 Hz), 6.65 (1H, m), 4.05-3.91 (4H, m), 2.68-2.53 (4H, m), 2.41 (3H, s). 36 IR ν_(max) (Nujol)/cm⁻¹ 3107, 3080, 2963, 2927, 2865, 1596, 1525, 1484, 1463, 1272 and 1236; NMR δ_(H) (400 MHz, CDCl₃) 7.97 (1H, d, J 5.5 Hz), 7.77 (1H, s), 7.48 (1H, m), 7.39 (1H, d, J 5.5 Hz), 6.67 (1H, m), 4.13 (1H, sept, J 7.0 Hz), 1.52 (3H, J 7.0 Hz). 37 95 mp 207-208° C.; IR ν_(max) (Nujol)/cm⁻¹ 3073, 2956, 1592, 1513, 1462 1263, 1012, 794 and 768; NMR δ_(H) (400 MHz, CDCl₃) 1.47 (3H, t, J 7.5 Hz), 3.28 (2H, q, J 7.5 Hz), 6.66 (1H, dd, J 3.5, 1.5 Hz), 7.49 (1H, d, J 5.5 Hz), 7.74-7.79 (1H, m) and 7.97 (1H, d, J 5.5 Hz) 38 75 mp 109-110° C.; IR ν_(max) (Nujol)/cm⁻¹ 3314, 2927, 1598, 1551, 1379, 1346, 1078, 795 and 744; NMR δ_(H) (400 MHz, CDCl₃) 1.60-1.80 (2H, m), 1.86-2.07 (2H, m), 2.14-2.26 (1H, m), 3.64-3.99 (4H, m), 4.38 (1H, m), 6.61-6.66 (2H, m), 7.22-7.28 (1H, m), 7.41 (1H, d, J 3.5 Hz), 7.74 (1H, d, J 2.5 Hz) and 7.88 (1H, d, J 5.5 Hz) 39 66 IR ν_(max) (Nujol)/cm⁻¹ 3058, 22925, 1595, 1524, 1462, 1268 and 794; NMR δ_(H) (400 MHz, CDCl₃) 2.69 (3H, s), 6.66 (1H, dd, J 4.0, 2.0 Hz), 7.42 (1H, d, J 5.5 Hz), 7.51 (1H, d, J 3.5 Hz), 7.76 (1H, d, J 2.5 Hz) and 7.98 (1H, d, J 5.5 Hz) 40 73 mp 101-102° C.; IR ν_(max) (Nujol)/cm⁻¹ 3255, 2925, 1610, 1550, 1515, 1446, 1331, 907 and 793; NMR δ_(H) (400 MHz, CDCl₃) 4.16-4.23 (2H, m), 5.16 (1H, dq, J 10.0, 1.5 Hz), 5.21-5.29 (1H, m); 5.32 (1H, dq, J 17.0, 1.5 Hz), 5.97-6.09 (1H, m), 6.63 (1H, dd, J 3.5, 2.0 Hz), 7.25 (1H, d, J 5.5 Hz), 7.39 (1H, d, J 3.5 Hz), 7.73 (1H, dd, J 2.5, 1.0 Hz) and 7.86 (1H, d, J 5.5 Hz) 41 56 mp 220.5-221.0° C.; IR ν_(max) (Nujol)/cm⁻¹ 3135, 3082, 3080, 1594, 1544, 1519, 1505, 1463, 1341, 1265, 867, 782 and 750; NMR δ_(H) (400 MHz, DMSO) 6.94-6.96 (1H, m), 7.75 (1H, dd, J 3.5, 1.0 Hz), 8.33 (1H, d, J 1.0 Hz), 9.79 (1H, s); Anal. Calcd for C₁₀H₄ClN₅O₃S₂O: C, 42.64; H, 1.43, N, 14.91. Found: C, 42.94; H, 1.81; N, 15.05. 42 IR ν_(max) (Nujol)/cm⁻¹ 3261, 2925, 2854, 1608, 1599, 1549, 1516, 1458, 1377 and 1329. NMR δ_(H) (400 MHz, CDCl₃) 7.86 (1H, d, J 5.5 Hz), 7.72 (1H, s), 7.38 (1H, m), 7.25 (1H, d, J 5.5 Hz), 7.65 (1H, m), 5.16 (1H, br s), 5.59 (2H, q, J 8.5 Hz), 1.32 (3H, t, J 8.5 Hz). 43 IR ν_(max) (Nujol)/cm⁻¹ 2956, 2925, 2855, 1598, 1547, 1521, 1508, 1478, 1458 and 1349; NMR δ_(H) (400 MHz, CDCl₃) 7.80 (1H, m), 7.72 (1H, m), 7.39 (1H, m), 7.22 (1H, m), 6.62 (1H, m), 3.68 (4H, m) and 2.02 (4H, m). 44 21 mp 182.8-183.8° C.; IR ν_(max) (Nujol)/cm⁻¹ 3152, 3128, 3107, 1601, 1558, 1543, 1498, 1477, 1406, 1321, 765 and 756; NMR δ_(H) (400 MHz, CDCl₃) 3.35 (6H, s), 6.65-6.67 (1H, m), 7.45 (1H, d, J 3.5 Hz), 7.74-7.75 (1H, m), 8.88 (1H, s); Anal. Calcd for C₁₂H₁₀N₄O₃S: C, 49.65; H, 3.47, N, 19.29. Found: C, 49.27; H, 3.49; N, 19.04. 45 IR ν_(max) (Nujol)/cm⁻¹ 3250, 3084, 2924, 2854, 1608, 1580, 1548, 1515, 1485, 1443 and 1330; NMR δ_(H) (400 MHz, CDCl₃) 8.59 (1H, m), 7.88 (1H, m), 7.72 (1H, m), 7.66 (1H, m), 7.41-7.38 (1H, m), 7.25 (1H, m), 7.18 (1H, m), 6.63 (1H, m), 6.21 (1H, br s) and 4.89 (2H, d, J 5.6 Hz). 46 44 IR ν_(max) (Nujol)/cm⁻¹ 3094, 2926, 2855, 1716, 1593, 1523, 1489, 1468, 1421, 1332 and 1190; NMR δ_(H) (400 MHz, CDCl₃) 8.00 (1H, m), 7.78 (1H, m), 7.50 (2H, m), 6.62 (1H, m), 4.15 (2H, m), 3.40 (2H, m), 2.95 (2H, m) and 1.20 (3H, t, J 7.0 Hz); M/Z 303 (M + H)⁺. 47 IR ν_(max) (Nujol)/cm⁻¹ 3417, 3103, 2974, 2944, 2859, 2820, 2776, 1599, 1556, 1538, 1488, 1462, 1337 and 1256. NMR δ_(H) (400 MHz, CDCl₃) 7.84 (1H, d, J 5.5 Hz), 7.73 (1H, s), 7.38 (1H, m), 7.22 (1H, d, J 5.5 Hz), 6.63 (1H, m), 5.64 (1H, br s), 3.60 (2H, q, J 6.0 Hz), 2.59 (2H, t, J 6.0 Hz), 2.28 (6H, s). 48 44 NMR δ_(H) (400 MHz, CDCl₃) 8.01 (1H, m), 7.79 (1H, m), 7.50 (2H, m), 6.80 (1H, m), 4.10 (1H, br m), 3.80 (2H, m), 3.30 (2H, m) and 2.18 (2H, m); Retention time 2.42 (80:20). 49 81 IR ν_(max) (Nujol)/cm⁻¹ 3079, 2923, 1745, 1729, 1698, 1594, 1531, 1466, 1336, 809; NMR δ_(H) (400 MHz, DMSO) 2.84 (2H, t, J 7.0 Hz), 3.24 (2H, t, J 7.0 Hz), 6.86 (1H, dd, J 1.8, 3.5 Hz), 7.54 (1H, dd, J 0.8, 3.5 Hz), 7.58 (1H, d, J 5.5 Hz), 8.17 (1H, dd, J 0.8, 1.8 Hz), 8.51 (1H, d, J 5.5 Hz), 12.05 (1H, br). 50 25 NMR δ_(H) (400 MHz, CDCl₃) 1.85 (2H, m), 1.95 (2H, m), 2.95 (2H, t, J 7.8 Hz), 3.50 (6H, m), 6.65 (1H, dd, J 1.7, 3.5 Hz), 7.48 (2H, m), 7.76 (1H, m), 7.99 (1H, d, J 5.5 Hz). 51 82 mp 145.8-146.5° C.; IR ν_(max) (Nujol)/cm⁻¹ 3403, 3310, 3135, 1600, 1551, 1517, 1463 and 750; NMR δ_(H) (400 MHz, CDCl₃) 3.30 (6H, s), 4.13 (2H, s), 6.59-6.61 (2H, m), 7.35 (1H, dd, J 3.5, 1.0 Hz), 7.68-7.71 (1H, m); Anal. Calcd for C₁₂H₁₂N₄OS + 0.3 H₂O: C, 54.24; H, 4.78, N, 21.08. Found: C, 54.37; H, 4.51; N, 20.93. 52 52 IR ν_(max) (Nujol)/cm⁻¹ 3070, 2924, 2854, 1541, 1464, 1352, 779, 650; NMR δ_(H) (400 MHz, CDCl₃) 1.50 (3H, t, J 7.50 Hz), 3.20 (2H, q, J 7.50 Hz), 7.45 (1H, m), 7.53 (1H, d, J 5.6 Hz), 7.92 (1H, m), 8.07 (1H, d, J 5.6 Hz), 8.79 (1H, m), 8.85 (1H, m). 53 IR ν_(max) (Nujol)/cm⁻¹ 2924, 2854, 1567, 1548, 1522, 1461, 1440, 1377 and 1353; NMR δ_(H) (400 MHz, CDCl₃) 7.80 (1H, d, J 5.5 Hz), 7.67 (1H, d, J 4.0 Hz), 7.26 (1H, d, J 5.5 Hz), 7.02 (1H, d, J 4.0 Hz), 3.28 (6H, s). 54 25 NMR δ_(H) (400 MHz, CDCl₃) 3.35 (2H, m), 4.12 (2H, m), 4.41 (1H, m), 6.65 (1H, d, J 1.8, 3.5 Hz), 7.46 (2H, m), 7.78 (1H, d, J 0.8, 1.8 Hz), 8.05 (1H, d, J 5.5 Hz). 55 52 mp 244.4-244.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3309, 3139, 1663, 1652, 1602, 1557, 1510, 1490, 1470, 1465, 1446, 1377 and 743; NMR δ_(H) (400 MHz, CDCl₃) 3.23 (6H, s), 6.61-6.63 (1H, m), 6.75 (1H, s), 7.17-7.22 (1H, m), 7.34-7.46 (5H, m), 7.72 (1H, s), 7.93 (1H, s), 8.04 (1H, s). 56 51 mp 210.9-211.3° C.; IR ν_(max) (Nujol)/cm⁻¹ 3346, 3140, 1666, 1558, 1541, 1462 and 1377; NMR δ_(H) (400 MHz, CDCl₃) 2.29 (3H, s), 3.31 (6H, s), 6.61-6.64 (1H, m), 7.39 (1H, d, J 3.5 Hz), 7.73 (1H, d, J 1.0 Hz), 8.25 (1H, s), 8.30 (1H, s); Anal. Calcd for C₁₄H₁₄N₄O₂S: C, 55.62; H, 4.67, N, 18.52. Found: C, 55.46; H, 4.57; N, 18.27. 57 47 mp 192.2-192.8° C.; IR ν_(max) (Nujol)/cm⁻¹ 3409, 3133, 3110, 1665, 1603, 1550, 1526, 1463, 1376 and 1261; NMR δ_(H) (400 MHz, CDCl₃) 3.33 (6H, s), 6.62-6.64 (1H, m), 7.40 (1H, dd, J 3.5, 1.0 Hz), 7.51-7.62 (3H, m), 7.73-7.74 (1H, m), 7.96-8.01 (2H, m), 8.45 (1H, s), 9.10 (1H, s); Anal. Calcd for C₁₉H₁₆N₄O₂S + 0.75 H₂O: C, 60.38; H, 4.67, N, 14.82. Found: C, 60.47; H, 4.63; N, 14.72. 58 65 mp 183.8-184.3° C.; IR ν_(max) (Nujol)/cm⁻¹ 3269, 3134, 3069, 1613, 1583, 1551, 1520, 1449 and 794; NMR δ_(H) (400 MHz, CDCl₃) 3.10 (3H, d, J 5.0 Hz), 5.09-5.10 (1H, s), 6.62-6.64 (1H, m), 7.26 (1H, d, J 4.5 Hz), 7.38 (1H, dd, J 3.5, 1.0 Hz), 7.71-7.73 (1H, m), 7.85 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₁H₉N₃OS + 0.3 H₂O: C, 55.82; H, 4.09, N, 17.75. Found: C, 55.85; H, 3.94; N, 17.68. 59 6 mp 211.9° C.; NMR δ_(H) (400 MHz, CDCl₃) 3.09 (3H, s), 6.72-6.74 (1H, m), 7.40 (1H, s), 7.63 (1H, d, J 3.5 Hz), 7.83 (1H, d, J 1.0 Hz), 7.90 (1H, s); M/Z 330 (M + H)⁺. 60 32 mp 108.3-108.6° C.; IR ν_(max) (Nujol)/cm⁻¹ 3104, 3073, 1702, 1667, 1598, 1545, 1467, 1373, 804 and 744; NMR δ_(H) (400 MHz, CDCl₃) 2.31 (3H, s), 3.66 (3H, s), 3.96 (2H, s), 6.68-6.70 (1H, m), 7.42 (1H, d, J 5.5 Hz), 7.47 (1H, d, J 3.5 Hz), 7.87 (1H, d, J 1.0 Hz), 8.07 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₅H₁₃N₃O₃S + 0.2 H₂O: C, 56.49; H, 4.23, N, 13.17. Found: C, 56.63; H, 4.14; N, 13.09; M/Z 316 (M + H)⁺. 61 23 NMR δ_(H) (400 MHz, CDCl₃) 3.69 (2H, q, J 5.5 Hz), 3.90 (2H, t, J 4.5 Hz), 5.47-5.58 (1H, m), 7.03 (1H, d, J 4.0 Hz), 7.24 (1H, d, J 5.5 Hz), 7.71 (1H, d, J 4.0 Hz) and 7.84 (1H, d, J 5.5 Hz); Retention time (80/20): 5.12min 62 82 IR ν_(max) (Nujol)/cm⁻¹ 2925, 2855, 1541, 1406, 1362, 783; NMR δ_(H) (400 MHz, CDCl₃) 2.93 (3H, s), 7.45 (1H, m), 7.51 (1H, d, J 5.6 Hz), 7.92 (1H, m), 8.07 (1H, d, J 5.6 Hz), 8.76 (1H, m), 8.85 (1H, m). 63 83 IR ν_(max) (Nujol)/cm⁻¹ 3048, 2926, 2855, 1541, 1468, 1335, 790; NMR δ_(H) (400 MHz, CDCl₃) 1.05 (3H, t, J 7.5 Hz), 2.00 (2H, sextet, J 7.5 Hz), 3.10 (2H, m), 7.45 (1H, m), 7.51 (1H, d, J 5.6 Hz), 7.92 (1H, m), 8.07 (1H, d, J 5.6 Hz), 8.76 (1H, m), 8.85 (1H, m). 64 26 IR ν_(max) (Nujol)/cm⁻¹ 3418, 3096, 2924, 1516, 1460, 1377, 1228, 827 and 795; NMR δ_(H) (400 MHz, CDCl₃) 7.55 (1H, d, J 6.0 Hz), 7.69 (1H, d, J 3.0 Hz), 8.18 (1H, d, J 3.0 Hz) and 8.20 (1H, d, J 5.5 Hz) 65 62 mp 152-153° C.; IR ν_(max) (Nujol)/cm⁻¹ 3056, 2925, 1566, 1532, 1464, 1354, 1132 and 792; NMR δ_(H) (400 MHz, CDCl₃) 3.32 (6H, s), 7.26 (1H, d, J 5.5 Hz), 7.54 (1H, d, J, 3.0 Hz), 7.91 (1H, d, J 5.5 Hz) and 8.10 (1H, d, J 3.0 Hz) 66 10 IR ν_(max) (Nujol)/cm⁻¹ 3057, 2956, 2855, 1530, 1467, 1450; NMR δ_(H) (400 MHz, CDCl₃) 7.45 (1H, m), 7.51 (1H, d, J 5.6 Hz), 7.92 (1H, m), 8.07 (1H, d, J 5.6 Hz), 8.76 (1H, m), 8.85 (1H, m), 9.28 (1H, s). 67 IR ν_(max) (Nujol)/cm⁻¹ 3288, 2956, 2925, 2554, 1597, 1584, 1557, 1523, 1459, 1427 and 1333. NMR δ_(H) (400 MHz, CDCl₃) 8.82 (1H, d, J 5.0 Hz), 8.57 (1H, d, J 8.0 Hz), 7.95 (1H, d, J 5.0 Hz), 7.92-7.82 (1H, m), 7.44 (7.40 (1H, m), 7.29-7.22 (1H, m), 5.60 (1H, br s), 4.10 (1H, br s), 3.95-3.92 (2H, m), 3.77-3.75 (2H, m). 68 87 mp 140-142° C.; IR ν_(max) (Nujol)/cm⁻¹ 3435, 2924, 1572, 1528, 1462, 1320, 1086, 793, 702 and 600; NMR δ_(H) (400 MHz, CDCl₃) 3.73 (2H, m), 3.93 (2H, t, J 5.0 Hz), 5.53-5.66 (1H, m), 7.24 (1H, d, J 5.5 Hz), 7.96 (1H, d, J 5.5 Hz) and 8.12 (1H, d, 3.0 Hz) 69 50 NMR δ_(H) (400 MHz, CDCl₃) 5.78 (1H, dd, J 1.8, 10.5 Hz), 6.68 (1H, dd, J 1.7, 3.5 Hz), 6.75 (1H, dd, J 1.8, 17.3 Hz), 7.05 (1H, dd, J 10.5, 17.3 Hz), 7.53 (1H, d, J 5.5 Hz), 7.55 (1H, dd, J 3.5, 5.5 Hz), 7.78 (1H, dd, J 0.8, 1.7 Hz), 8.01 (1H, d, J 5.5 Hz). 70 16 IR ν_(max) (Nujol)/cm⁻¹ 3072, 2923, 1696, 1540, 1464, 788; NMR δ_(H) (400 MHz, CDCl₃) 1.50 (6H, d, J 6.9 Hz), 3.44 (1H, heptet, J 6.9 Hz), 7.44 (1H, ddd, J 1.3, 4.9, 7.5 Hz), 7.54 (1H, d, J 5.5 Hz), 7.93 (1H, dt, J 1.3, 7.5 Hz), 8.06 (1H, d, J 5.5 Hz), 8.81 (1H, m), 8.85 (1H, m). 71 13 mp 65.0-65.4° C.; IR ν_(max) (Nujol)/cm⁻¹ 3326, 3090, 1598, 1558, 1488, 1466, 1330 and 1088; NMR δ_(H) (400 MHz, CDCl₃) 3.41 (3H, s), 3.63 (2H, t, J 5.5 Hz), 3.79 (2H, q, J 5.5 Hz), 5.61 (1H, t, J 5.0 Hz), 6.63-6.65 (1H, m), 7.38 (1H, d, J 3.0 Hz), 7.72-7.73 (1H, m), 7.84 (1H, s); Anal. Calcd for C₁₃H₁₂N₃BrO₂S: C, 44.08; H, 3.41, N, 11.86. Found: C, 43.89; H, 3.48; N, 11.77. 72 42 mp 75.4-76.3° C.; IR ν_(max) (Nujol)/cm⁻¹ 3288, 3098, 1597, 1548, 1516, 1462, 1376, 1341 and 767; NMR δ_(H) (400 MHz, CDCl₃) 1.68-1.80 (1H, m), 1.83-2.08 (2H, m), 2.17-2.28 (1H, m), 3.65-3.81 (2H, m), 3.82-3.90 (1H, m), 3.97-4.07 (1H, m), 4.34-4.43 (1H, m), 6.63-6.65 (1H, m), 7.42 (1H, d, J 1.0 Hz), 7.73-7.74 (1H, m), 7.85 (1H, s). 73 68 IR ν_(max) (Nujol)/cm⁻¹ 3061, 2925, 2854, 1727, 1595, 1523, 1484, 1467, 1377 and 1230; NMR δ_(H) (400 MHz, CDCl₃) 8.15 (1H, m), 7.82 (1H, m), 7.74 (1H, m), 7.70 (1H, m), 6.70 (1H, m), 4.60 (2H, q, J 7.0 Hz), and 1.50 (3H, t, J 7.0 Hz). 74 47 NMR δ_(H) (400 MHz, CDCl₃) 1.43 (9H, s), 3.42 (2H, q, J 5.5 Hz), 3.65 (2H, q, J 5.5 Hz), 5.34 (1H, t, J 5.5 Hz), 6.63 (1H, dd, J 2.0, 3.5 Hz), 7.20 (1H, d, J 5.5 Hz), 7.39 (1H, d, J 3.5 Hz), 7.72 (1H, dd, J 1.0, 1.5 Hz) and 7.85 (1H, d, J 5.5 Hz); Retention time 3.26min (8:2) 75 67 NMR δ_(H) (400 MHz, CDCl₃) 1.40 (2H, br s), 2.99 (2H, t, J 6.0 Hz), 3.60 (2H, q, J 6.0 Hz), 5.40 (1H, t, J 5.5 Hz), 6.63 (1H, dd, J 2.0, 3.5 Hz), 7.22 (1H, d, J 5.5 Hz), 7.37 (1H, d, J 3.5 Hz), 7.72 (1H, dd, J 1.0, 2.0 Hz) and 7.84 (1H, d, J 5.5 Hz); Retention time 2.65min (7:3) 76 49 mp 112-113° C.; IR ν_(max) (Nujol)/cm⁻¹ 3089, 2925, 1561, 1352, 1136 and 794; NMR δ_(H) (400 MHz, CDCl₃) 2.60 (3H, s), 3.31 (6H, s), 7.09 (1H, s), 7.24 (1H, d, J 5.5 Hz) and 7.90 (1H, d, J 5.5 Hz) 77 5 NMR δ_(H) (400 MHz, CDCl₃) 3.61 (2H, q, J 6.0 Hz), 3.75 (2H, q, J 6.0 Hz), 5.56 (1H, t, J 6.0 Hz), 6.65 (1H, dd, J 1.5, 3.5 Hz), 7.21 (1H, d, J 5.5 Hz), 7.39 (1H, d, J 3.5 Hz) 7.75 (1H, dd, J 1.0, 2.0 Hz), 7.92 (1H, d, J 5.5 Hz) and 9.31 (1H, br s); Retention time 2.89min (80:20) 78 51 mp 155-156° C.; NMR δ_(H) (400 MHz, CDCl₃) 3.86 (3H, s), 3.87 (3H, s), 4.68 (2H, d, J 5.5 Hz), 5.40 (1H, t, J 5.5 Hz), 6.62-6.64 (1H, m), 6.82 (1H, d, J 8.0 Hz), 6.94-6.99 (2H, m), 7.24 (1H, d, J 5.5 Hz), 7.37 (1H, dd, J 3.5, 1.0 Hz), 7.72-7.73 (1H, m), 7.86 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₉H₁₇N₃O₃S: C, 62.11; H, 4.66, N, 11.43. Found: C, 62.19; H, 4.67; N, 11.44. 79 92 mp 169.6-169.9° C.; NMR δ_(H) (400 MHz, CDCl₃) 5.02 (2H, s), 6.63-6.66 (1H, m), 7.22 (1H, d, J 5.5 Hz), 7.39 (1H, dd, J 3.5, 1.0 Hz), 7.22-7.74 (1H, m), 7.89 (1H, d, J 5.5 Hz); Anal. Calcd for C₁₀H₇N₃OS + 0.2 H₂O: C, 54.38; H, 3.38, N, 19.03. Found: C, 54.69; H, 3.35; N, 18.74. 80 45 IR ν_(max) (Nujol)/cm⁻¹ 2925, 2855, 1545, 1464, 1356; NMR δ_(H) (400 MHz, CDCl₃) 1.45 (3H, t, J 7.5 Hz), 2.61 (3H, s), 3.15 (2H, q, J 7.5 Hz), 7.15 (1H, s), 7.50 (1H, d, J 5.5 Hz), 8.02 (1H, d, J 5.5 Hz). 81 20 NMR δ_(H) (400 MHz, CDCl₃) 8.08 (1H, m), 7.80 (1H, m), 7.55 (2H, m), 6.70 (1H, m), 4.90 (2H, s) and 3.80 (1H, br m); Retention time 3.06 (80:20). 82 37 IR ν_(max) (Nujol)/cm⁻¹ 3050, 2925, 2855, 1543, 1526, 1460, 1356; NMR δ_(H) (400 MHz, CDCl₃) 1.45 (3H, t, J 7.5 Hz), 3.18 (2H, q, J 7.5 Hz), 7.54 (1H, d, J 7.5 Hz), 7.61 (1H, d, J 3.1 Hz), 8.09 (1H, d, J 7.5 Hz), 8.15 (1H, d, J 3.1 Hz). 83 IR ν_(max) (Nujol)/cm⁻¹ 3287, 3089, 2924, 2854, 1633, 1603, 1548, 1516, 1486, 1462, 1377 and 1331; NMR δ_(H) (400 MHz, CDCl₃) 1.93 (3H, s), 3.54 (2H, q, J 5.5 Hz), 3.69 (2H, q, J 5.5 Hz), 5.43 (1H, t, J 6.0 Hz), 6.65 (1H, dd, J 1.5, 3.5 Hz), 6.76 (1H, br s), 7.22 (1H, d, J 5.5 Hz), 7.39 (1H, dd, J 1.0, 3.5 Hz), 7.73 (1H, dd, J 1.0, 1.5 Hz) and 7.89 (1H, d, J 5.5 Hz); Retention time 3.08min (70:30). 84 IR ν_(max) (Nujol)/cm⁻¹ 3317, 3265, 2924, 2854, 1635, 1613, 1580, 1558, 1514, 1463, 1377 and 1335; NMR δ_(H) (400 MHz, CDCl₃), 0.90 (6H, d, J 5.5 Hz), 2.01 (2H, m), 2.07 (1H, m), 3.56 (2H, q, J 5.5 Hz), 3.68 (2H, q, J 5.5 Hz), 5.49 (1H, t, J 6.0 Hz), 6.65 (1H, dd, J 1.5, 3.5 Hz), 7.21 (1H, d, J 5.5 Hz), 7.39 (1H, dd, J 1.0, 3.5 Hz), 7.73 (1H, dd, J 1.0, 1.5 Hz) and 7.89 (1H, d, J 5.5 Hz); Retention time 4.43min (70:30). 85 IR ν_(max) (Nujol)/cm⁻¹ 3318, 3083, 2974, 2871, 1644, 1600 1549, 1488, 1461 and 1337; NMR δ_(H) (400 MHz, CDCl₃) 3.75 (2H, q, J 5.5 Hz), 3.83 (2H, q, J 5.5 Hz), 5.68 (1H, t, J 5.0 Hz), 6.62 (1H, dd, J 1.5, 3.5 Hz), 7.21 (1H, d, J 5.5 Hz), 7.29 (2H, m), 7.38 (2H, m), 7.71 (3H, m), 7.87 (1H, m) and 7.90 (1H, d, J 5.5 Hz); Retention time 5.05min (70:30). 86 IR ν_(max) (Nujol)/cm⁻¹ 3267, 3108, 2925, 2854, 1641, 1611, 1548, 1517, 1485, 1464, 1422 and 1334; NMR δ_(H) (400 MHz, CDCl₃) 3.71 (2H, q, J 5.5 Hz), 3.81 (2H, q, J 5.5 Hz), 5.65 (1H, t, J 6.0 Hz), 6.63 (1H, dd, J 1.5, 3.5 Hz), 6.92 (1H, m), 7.24 (1H, d, J 5.5 Hz), 7.37 (3H, m), 7.56 (1H, br s), 7.72 (1H, dd, J 1.0, 1.5 Hz) and 7.89 (1H, d, J 5.5 Hz); Retention time 4.79min. (70:30). 87 NMR δ_(H) (400 MHz, CDCl₃) 3.52 (2H, m), 3.64 (3H, s), 3.79 (2H, m), 5.53 (1H, br s), 6.73 (1H, dd, J 1.5, 3.5 Hz), 7.34 (1H, d, J 5.5 Hz), 7.65 (1H, m), 7.83 (1H, m) and 8.02 (1H, d, J 5.5 Hz); Retention time 3.46min. (70:30). 88 NMR δ_(H) (400 MHz, CDCl₃) 0.87 (6H, d, J 6.4 Hz), 1.83 (2H, m), 3.52 (2M, q, J 5.5 Hz), 3.73 (2H, m), 3.85 (2H, m), 5.50 (1H, br s) 6.71 (1H, dd, J 1.5, 3.5 Hz), 7.32 (1H, d, J 5.5 Hz), 7.61 (1H, m), 7.81 (1H, m) and 7.96 (1H, d, J 5.5 Hz); Retention time 5.69min. (70:30). 89 99 NMR δ_(H) (400 MHz, CDCl₃) 3.55 (2H, q, J 5.8 Hz), 3.78 (2H, q, J 5.8 Hz), 5.07 (2H, s), 5.55 (1H, m), 6.73 (1H, dd, J 1.5, 3.5 Hz), 7.29 (5H, m), 7.40 (1H, d, J 5.5 Hz), 7.76 (1H, m), 7.85 (1H, m), 8.11 (1H, d, J 5.5 Hz) and 10.05 (1H, br s); Retention time 6.16min (70:30) 90 NMR δ_(H) (400 MHz, CDCl₃) 3.01 (1H, t, J 5.8 Hz), 3.60 (2H, q, J 5.5 Hz), 4.04 (2H, d, J 5.8 Hz), 4.11 (2H, q, J 5.5 Hz), 5.46 (1H, m), 6.61 (1H, dd, J 1.5, 3.5 Hz), 7.31 (1H, d, J 5.5 Hz), 7.33-7.45 (4H, m), 7.71-7.79 (4H, m) and 7.82 (1H, d, J 5.5 Hz); Retention time 17.2min (70:30). 91 NMR δ_(H) (400 MHz, DMSO) 3.27 (2H, m), 3.42 (2H, m), 3.63 (2H, m), 5.01 (1H, m), 5.08 (1H, m), 5.77 (1H, m), 6.10 (1H, br s), 6.85 (1H, dd, J 1.5, 3.5 Hz), 7.29 (1H, d, J 5.5 Hz), 7.48 (2H, m), 8.17 (1H, m) and 8.35 (1H, d, J 5.5 Hz); Retention time 3.39min. (70:30). 92 99 NMR δ_(H) (400 MHz, DMSO) 3.30 (2H, t, J 6.0 Hz), 3.45 (2H, t, J 6.0 Hz), 4.23 (2H, s), 6.46 (1H, br s), 6.85 (1H, dd, J 2.0, 3.5 Hz), 7.18-7.33 (7H, m), 7.49 (2H, m), 8.17 (1H, m) and 8.36 (1H, d, J 5.5 Hz); Retention time 4.61min (7:3) 93 NMR δ_(H) (400 MHz, DMSO) 1.02-1.25 (5H, m), 1.51-1.78 (5H, m), 3.26 (2H, m), 3.34 (1H, m), 3.43 (2H, m), 5.75 (1H, br s), 6.78 (1H, br s), 6.87 (1H, dd, J 1.5, 3.5 Hz), 7.34 (1H, d, J 5.5 Hz), 7.49 (1H, m), 7.96 (1H, br s), 8.15 (1H, m) and 8.36 (1H, d, J 5.5 Hz); Retention time 5.30min, (70:30). 94 NMR δ_(H) (400 MHz, DMSO) 3.35 (2H, m), 3.44 (2H, m), 6.30 (1H, t, J 6.0 Hz), 6.79 (1H, dd, J 1.5, 3.5 Hz), 7.17-7.31 (5H, m), 7.36-7.47 (3H, m), 8.10 (1H, m), 5.27 (1H, d, J 5.5 Hz) and 8.52 (1H, m); Retention time 5.46min, (70:30). 95 NMR δ_(H) (400 MHz, DMSO) 3.35 (2H, q, J 5.8 Hz), 3.46 (2H, q, J 5.8 Hz), 6.35 (1H, t, J 6.0 Hz), 6.80 (1H, dd, J 1.5, 3.5 Hz), 7.19 (1H, m), 7.25 (3H, m), 7.41 (3H, m), 8.10 (1H, dd, J 1.0, 1.5 Hz), 8.28 (1H, d, J 5.5 Hz) and 8.70 (1H, m); Retention time 9.61min. (70:30). 96 NMR δ_(H) (400 MHz, CDCl₃) 3.56 (2H, q, J 5.8 Hz), 3.78 (2H, m), 5.07 (2H, s), 5.55 (1H, br s), 6.73 (1H, dd, J 1.5, 3.5 Hz), 7.29-7.36 (5H, m), 7.39 (1H, d, J 5.5 Hz), 7.76 (1H, m), 7.85 (1H, m) 8.11 (1H, d, J 5.5 Hz) and 10.07 (1H, br s); Retention time 6.16min (70:30). 97 NMR δ_(H) (400 MHz, DMSO) 3.58 (2H, m), 3.76 (2H, m), 6.80 (1H, dd, J 1.5, 3.5 Hz), 7.22 (1H, d, J 5.5 Hz), 7.35 (4H, m), 7.42 (3H, m), 7.96 (1H, m) 8.11 (1H, m), 8.27 (1H, d, J 5.5 Hz) and 9.68 (1H, br s); Retention time 8.41min, (70:30). 98 NMR δ_(H) (400 MHz, DMSO) 2.93 (3H, s), 3.21 (2H, m), 3.64 (2H, m), 6.86 (1H, dd, J 1.5, 3.5 Hz), 7.18 (1H, m), 7.32 (1H, m), 7.52 (1H, m), 7.86 (1H, m), 8.17 (1H, m) and 8.37 (1H, m); Retention time 2.93min (70:30). 99 NMR δ_(H) (400 MHz, CDCl₃) 1.21 (9H, s), 3.28 (2H, q, J 5.8 Hz), 3.61 (2H, q, J 5.9 Hz), 5.41 (1H, t, J 6.0 Hz), 6.58 (1H, t, J 6.0 Hz) 6.65 (1H, dd, J 1.5, 3.5 Hz), 7.23 (1H, d, J 5.5 Hz), 7.40 (3H, m), 7.69 (2H, d, J 6.4 Hz), 7.74 (1H, m) and 7.87 (1H, d, J 5.5 Hz); Retention time 10.30min 100 35 NMR δ_(H) (400 MHz, CDCl₃) 8.88 (1H, m), 8.70 (1H, m), 8.08 (1H, m), 7.88 (1H, m), 7.82 (1H, m), 7.78 (1H, m), 7.64 (2H, m) and 6.30 (1H, m); Retention time 3.52 (80:20). 101 80 mp 193.9-195.0° C.; IR ν_(max) (Nujol)/cm⁻¹ 3246, 3149, 3080, 3064, 1683, 1664, 1599, 1547, 1497, 1315 and 1298; NMR δ_(H) (400 MHz, DMSO) 2.26 (3H, s), 6.86-6.88 (1H, m), 7.51 (1H, d, J 3.0 Hz), 7.48 (1H, d, J 5.5 Hz), 8.20 (1H, s), 8.51 (1H, d, J 5.5 Hz), 10.58 (1H, s); Anal. Calcd for C₁₂H₉N₃O₂S + 0.5 H₂O: C, 53.72; H, 3.76, N, 15.66. Found: C, 53.81; H, 3.44; N, 15.41. 102 Mp 243-244° C., IR ν_(max) (Nujol)/cm⁻¹ 2955, 2924, 2854, 1543, 1526, 1574, 1468, 1435, 1358 and 1236. NMR δ_(H) (400 MHz, CDCl₃) 8.18 (1H, d, J 5.5 Hz), 7.82 (1H, s), 7.53 (1H, d, J 5.5 Hz), 2.63 (3H, s). 103 Mp 240-241° C., IR ν_(max) (Nujol)/cm⁻¹ 2955, 2925, 2854, 1537, 1516, 1481, 1460, 1359 and 1230. NMR δ_(H) (400 MHz, CDCl₃) 8.15 (1H, d, J 5.5 Hz), 7.51 (1H, d, J 5.5 Hz), 2.50 (6H, s). 104 71 mp 208-211° C.; IR ν_(max) (Nujol)/cm⁻¹ 2855, 1567, 1520, 1358, 1101, 817 and 794; NMR δ_(H) (400 MHz, CDCl₃) 2.57 (3H, d, J 1.0 Hz), 3.30 (6H, s), 7.24 (1H, d, J 5.5 Hz), 7.74 (1H, d, J 1.5 Hz) and 7.89 (1H, d, J 5.5 Hz) 105 99 Mp 148-149° C.; IR ν_(max) (Nujol)/cm⁻¹ 2854, 1564, 1356, 1236 and 7932; NMR δ_(H) (400 MHz, CDCl₃) 2.45 (3H, s), 2.47 (3H, s), 3.30 (6H, s), 7.23 (1H, d, J 5.5 Hz) and 7.87 (1H, d, J 5.5 Hz) 106 Mp 170-170.5° C.; IR ν_(max) (Nujol)/cm⁻¹ 3061, 2955, 2925, 2854, 1545, 1519, 1480, 1465, and 1377. NMR δ_(H) (400 MHz, CDCl₃) 8.09 (1H, d, J 5.5 Hz), 7.88 (2H, d, J 7.0 Hz), 7.71 (1H, s), 7.57 (1H, d, J 5.5 Hz), 7.50 (2H, t, J 7.5 Hz), 7.42 (1H, t, J 7.5 Hz), 3.25 (2H, q, J 7.5 Hz), 1.53 (3H, t, J 7.5 Hz). 107 Mp 258-258.5° C.; IR ν_(max) (Nujol)/cm⁻¹ 3136, 3073, 2955, 2924, 2854, 1573, 1559, 1514, 1475, 1408, 1335 and 1251. NMR δ_(H) (400 MHz, CDCl₃) 10.43 (1H, br s), 7.91 (1H, d, J 5.5 Hz), 7.43 (1H, s), 7.25-7.21 (2H, m), 3.30 (6H, s) 108 80 Mp 178.7-179.5° C.; IR ν_(max) (Nujol)/cm⁻¹ 3245, 2924, 2845, 1600, 1554, 1530, 1515, 1467, 1344, 1321, 1251 and 1232, NMR δ_(H) (400 MHz, CDCl₃) 8.11 (1H, d, J 3.2 Hz), 7.97 (1H, m), 7.55 (1H, d, J 3.2 Hz), 7.25 (1H, s), 7.00 (1H, s), 6.98 (1H, m), 6.84 (1H, m), 5.46 (1H, t, J 5.6 Hz), 4.70 (2H, d, J 6.0 Hz), 3.87 (3H, s) and 3.87 (3H, s); Anal Calcd. for C₁₈H₁₆N₄O₂S₂: C, 56.23; H, 4.19; N, 14.57. Found: C, 56.23; H, 4.11; N 14.41. 109 Mp 221-222° C.; IR ν_(max) (Nujol)/cm⁻¹ 3083, 2925, 2854, 1528, 1519, 1461, 1377, 1303, 1241 and 1161. NMR δ_(H) (400 MHz, CDCl₃) 8.68 (1H, s), 8.63 (1H, d, J 8.0 Hz), 8.17 (1H, d, J 5.5 Hz), 7.74 (1H, d, J 8.0 Hz), 7.52 (1H, d, J 5.5 Hz), 2.48 (3H, s). 110 63 mp 190.1-190.7° C.; IR ν_(max) (Nujol)/cm⁻¹ 3464, 3296, 3165, 3122, 3038, 1635, 1555, 1541, 1481 and 1360; NMR δ_(H) (400 MHz, CDCl₃) 5.10 (2H, s), 7.24 (1H, d, J 5.5 Hz), 7.58 (1H, d, J 3.0 Hz), 7.98 (1H, d, J 5.5 Hz), 8.12 (1H, d, J 3.0 Hz); Anal. Calcd for C₉H₆N₄S₂: C, 46.14; H, 2.58, N, 23.90. Found: C, 46.14; H, 2.67; N, 23.02. 111 85 mp 139.3-139.7° C.; IR ν_(max) (Nujol)/cm⁻¹ 3326, 3118, 3078, 3062, 1557, 1537, 1506, 1356 and 795; NMR δ_(H) (400 MHz, CDCl₃) 1.75-7.84 (1H, m), 1.91-2.10 (2H, m), 2.15-2.26 (1H, m), 3.70-3.82 (2H, m), 3.84-3.98 (2H, m), 4.38-4.56 (1H, s), 7.24 (1H, d, J 5.5 Hz), 7.56 (1H, d, J 3.5 Hz), 7.95 (1H, d, J 5.5 Hz), 8.12 (1H, d, J 3.5 Hz); Anal. Calcd for C₁₄H₁₄N₄OS₂: C, 52.81; H, 4.43, N, 17.59. Found: C, 53.08; H, 4.53; N, 17.22. 112 62 mp 128-129° C.; IR ν_(max) (Nujol)/cm⁻¹ 3251, 3102, 3076, 3019, 1596, 1552, 1528, 1448, 1336 and 794; NMR δ_(H) (400 MHz, CDCl₃) 4.19-4.24 (2H, m), 5.14-5.37 (3H, m), 5.99-6.10 (1H, m), 7.24 (1H, d, J 5.5 Hz), 7.56 (1H, d, J 3.0 Hz), 7.95 (1H, d, J 5.5 Hz), 8.11 (1H, d, J 3.0 Hz). 113 84 mp 90.6-90.7° C.; IR ν_(max) (Nujol)/cm⁻¹ 3056, 2961, 2855, 1546, 1529, 1480, 806; NMR δ_(H) (400 MHz, CDCl₃) 1.48 (6H, d, J 6.9 Hz), 3.40 (1H, heptet, J 6.9 Hz), 7.55 (1H, d, J 5.5 Hz), 7.59 (1H, d, J 3.1 Hz), 8.08 (1H, d, J 5.5 Hz), 8.14 (1H, d, J 3.1 Hz). 114 7 IR ν_(max) (Nujol)/cm⁻¹ 2925, 2854, 1615, 1545, 1498, 1459, 1377, 1265 and 1174; NMR δ_(H) (400 MHz, CDCl₃) 8.05 (1H, m), 7.80 (1H, m), 7.60 (2H, m), 7.00 (1H, m), 3.83 (3H, s), 3.25 (2H, q, J 7.0 Hz) and 1.50 (3H, t, J 7.0 Hz). 115 93 mp 133-133.5° C.; IR ν_(max) (Nujol)/cm⁻¹ 2925, 1553, 1467, 1404, 1356, 1241 and 796; NMR δ_(H) (400 MHz, CDCl₃) 2.44 (3H, s), 3.35 (6H, s), 7.25 (1H, d, J 5.5 Hz), 7.67 (1H, dd, J 7.5, 2.5 Hz), 7.89 (1H, d, J 5.5 Hz), 8.54 (1H, d, J 8.5 Hz) and 8.64 (1H, d, J 2.0 Hz) 116 37 mp 242.6-243.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3251, 3079, 3060, 1687, 1672, 1560, 1496 and 1320; NMR δ_(H) (400 MHz, DMSO) 2.29 (3H, s), 7.54 (1H, d, J 5.5 Hz), 8.15 (1H, d, J 3.5 Hz), 8.27 (1H, d, J 3.0 Hz), 8.56 (1H, d, J 5.5 Hz), 10.68 (1H, s). 117 67 Mp 149° C.; IR ν_(max) (Nujol)/cm⁻¹ 2955, 2925, 2854, 1595, 1523, 1485, 1468 and 1333; NMR δ_(H) (400 MHz, CDCl₃) 8.00 (1H, m), 7.76 (1H, m), 7.60 (1H, m), 7.56 (1H, m), 7.36 (1H, m), 7.05 (1H, m), 6.92 (1H, m), 6.63 (1H, m) and 4.59 (2H, s). 118 IR ν_(max) (Nujol)/cm⁻¹ 3036, 2925, 2854, 1535, 1481, 1468, 1351, 1129 and 1098; NMR δ_(H) (400 MHz, CDCl₃) 9.01 (1H, m), 8.78 (1H, s), 8.01 (1H, d, J 5.6 Hz), 7.57 (1H, d, J 5.2 Hz), 3.13 (2H, q, J 7.6 Hz) and 1.47 (3H, t, J 7.6 Hz). 119 3 Mp 179° C.; IR ν_(max) (Nujol)/cm⁻¹ 3057, 2924, 2854, 1525, 1465, 1438, 1378 and 1296; NMR δ_(H) (400 MHz, CDCl₃) 8.12 (2H, m), 7.58 (2H, m), 3.30 (4H, q, J 7.0 Hz) and 1.60 (6H, t, J 7.0 Hz); M/Z 327 (M + H)⁺. 120 IR ν_(max) (Nujol)/cm⁻¹ 3388, 3060, 2924, 2855, 1662, 1561, 1541, 1461, 1376, 1356, 1309, 1266 and 1096. NMR δ_(H) (400 MHz, CDCl₃) 8.32 (1H, br s), 8.13 (1H, d, J 5.5 Hz), 7.58 (1H, J 5.5 Hz), 7.26 (1H, s), 3.19 (2H, q, J 7.5 Hz), 1.48 (3H, t, J 7.5 Hz). 121 39 mp 178.6-179.6° C.; IR ν_(max) (Nujol)/cm⁻¹ 3080, 2925, 1569, 1525, 1468, 1092, 854, 815 and 750; NMR δ_(H) (400 MHz, CDCl₃) 1.47 (3H, t, J 7.5 Hz), 3.11 (2H, q, J 7.5 Hz), 7.29 (1H, s), 7.47 (1H, s), 7.51 (1H, d, J, 5.5 Hz), 8.07 (1H, d, J 5.5 Hz) and 10.65 (1H, br s) 122 13 Mp 131° C.; IR ν_(max) (Nujol)/cm⁻¹ 2960, 1547, 1529, 1377, 1314, 1301 and 1096; NMR δ_(H) (400 MHz, CDCl₃) 8.24 (1H, m), 8.12 (1H, m), 8.02 (1H, m), 7.48-7.60 (3H, m), 3.20 (2H, q, J 7.0 Hz) and 1.50 (3H, t, J 7.0 Hz). 123 73 IR ν_(max) (Nujol)/cm⁻¹ 3392, 3254, 1681, 1586, 1552, 1515, 1342, 1318, 1274, 1252, 1165 and 1150; NMR δ_(H) (400 MHz, CDCl₃) 1.43 (9H, s), 3.46 (2H, q, J 5.5 Hz), 3.70 (2H, q, J 5.5 Hz), 5.12 (1H, br s), 5.42 (1H, t, J 5.5 Hz), 7.23 (1H, d, J 5.5 Hz), 7.55 (1H, d, J 3.5 Hz), 7.95 (1H, d, J 5.5 Hz) and 8.11 (1H, d, J 3.0 Hz); Retention time 5.17min (70:30) 124 60 IR ν_(max) (Nujol)/cm⁻¹ 3352, 3241, 3045, 1558, 1349, 1315, 1280 and 1116; NMR δ_(H) (400 MHz, CDCl₃) 1.27 (2H, br s), 3.02 (2H, t, J 6.0 Hz), 3.63 (2H, q, J 6.0 Hz), 5.46 (1H, m), 7.23 (1H, d, J 5.5 Hz), 7.55 (1H, d, J 3.5 Hz), 7.94 (1H, d, J 5.5 Hz) and 8.11 (1H, d, J 3.5 Hz); Retention time 2.35min (60:40) 125 61 NMR δ_(H) (400 MHz, DMSO) 1.81 (3H, s), 3.30 (2H, q, J 6.0 Hz), 3.44 (2H, q, J 6.0 Hz), 7.28 (2H, m), 7.97 (1H, m), 8.07 (1H, d, J 3.0 Hz), 8.21 (1H, d, J 3.0 Hz) and 8.32 (1H, d, J 5.5 Hz); Retention time 2.83min (70:30) 126 NMR δ_(H) (400 MHz, DMSO) 0.97 (3H, t, J 7.2 Hz), 3.00 (2H, m), 3.26 (2H, q, J 6.0 Hz), 3.40 (2H, q, J 6.0 Hz), 5.86 (1H, t, J 5.5 Hz), 5.96 (1H, t, J 5.5 Hz), 7.29 (2H, m), 8.08 (1H, d, J 3.2 Hz), 8.22 (1H, d, J 3.3 Hz) and 8.32 (1H, d, J 5.5 Hz); Retention time 2.42 (80:20). 127 NMR δ_(H) (400 MHz, DMSO) 3.30 (2H, q, J 5.8 Hz), 3.42 (2H, q, J 5.8 Hz), 3.63 (2H, m), 5.00 (1H, dd, J 1.6, 10.2 Hz), 5.09 (1H, dd, J 1.8, 17.2 Hz), 5.79 (1H, m), 6.05 (2H, m), 7.29 (2H, m) 8.08 (1H, d, J 3.1 Hz), 8.22 (1H, d, J 3.1 Hz) and 8.32 (1H, d, J 5.5 Hz); Retention time 2.50min (80:20). 128 81 NMR δ_(H) (400 MHz, DMSO) 0.99-1.28 (5H, m), 1.48-1.74 (5H, m), 3.25 (2H, q, J 6.0 Hz), 3.33 (1H, m), 3.39 (2H, q, J 6.0 Hz), 5.77 (1H, d, J 8.0 Hz), 5.86 (1H, t, J 5.5 Hz), 7.28 (1H, m), 8.07 (1H, d, J 3.0 Hz), 8.21 (1H, d, J 3.0 Hz) and 8.31 (1H, d, J 5.5 Hz); Retention time 3.11min (80:20) 129 42 NMR δ_(H) (400 MHz, DMSO) 0.84 (6H, d, J 6.5 Hz), 1.95 (3H, m), 3.37 (2H, m), 3.43 (2H, q, J 6.0 Hz), 7.26 (2H, m), 7.89 (1H, m), 8.08 (1H, d, J 3.0 Hz), 8.21 (1H, d, J 3.0 Hz) and 8.32 (1H, d, J 5.5 Hz); Retention time 2.77min (80:20) 130 58 NMR δ_(H) (400 MHz, DMSO) 3.25 (2H, q, J 6.0 Hz), 3.44 (2H, q, J 6.0 Hz), 3.52 (3H, s), 7.21 (1H, t, J 5.5 Hz), 7.26 (1H, d, J 5.5 Hz), 7.30 (1H, m), 8.07 (1H, d, J 3.0 Hz), 8.21 (1H, d, J 3.0 Hz) and 8.32 (1H, d, J 5.5 Hz); Retention time 2.53min (80:20) 131 62 NMR δ_(H) (400 MHz, DMSO) 0.84 (6H, d, J 6.5 Hz), 1.79 (1H, m), 3.25 (2H, q, J 6.0 Hz), 3.45 (2H, q, J 6.0 Hz), 3.71 (2H, d, J 6.5 Hz), 7.16 (1H, t, J 5.5 Hz), 7.26 (1H, d, J 5.5 Hz), 7.30 (1H, m), 8.07 (1H, d, J 3.0 Hz), 8.21 (1H, d, J 3.0 Hz) and 8.32 (1H, d, J 5.5 Hz); Retention time 3.23min (80:20) 132 NMR δ_(H) (400 MHz, DMSO) 1.21 (9H, s), 3.24 (2H, q, J 5.8 Hz), 3.39 (2H, q, J 5.8 Hz), 5.68 (1H, s), 5.80 (1H, t, J 6.0 Hz), 7.28 (2H, m), 8.07 (1H, d, J 3.1 Hz), 8.22 (1H, d, J 3.1 Hz), and 8.32 (1H, d, J 5.5 Hz); Retention time 2.83min, (80:20). 133 95 NMR δ_(H) (400 MHz, DMSO) 3.30 (2H, q, J 6.0 Hz), 3.42 (2H, q, J 6.0 Hz), 4.20 (2H, d, J 5.6 Hz), 6.10 (1H, t, J 5.9 Hz), 6.41 (1H, t, J 6.0 Hz), 7.16-7.33 (7H, m), 8.07 (1H, d, J 3.5 Hz), 8.21 (1H, d, J 3.0 Hz) and 8.31 (1H, d, J 5.5 Hz); Retention time 2.87min (80:20) 134 NMR δ_(H) (400 MHz, DMSO) 3.38 (2H, q, J 5.8 Hz), 3.47 (2H, q, J 5.8 Hz), 6.29 (1H, t, J 6.0 Hz), 6.88 (1H, t, J 6.0 Hz), 7.21 (1H, t, J 6.0 Hz), 7.27 (3H, m), 7.37 (3H, m), 8.07 (1H, d, J 3.1 Hz), 8.22 (1H, d, J 3.2 Hz) and 8.32 (1H, d, J 5.5 Hz); Retention time 3.22min (80:20). 135 NMR δ_(H) (400 MHz, DMSO) 3.38 (2H, q, J 5.8 Hz), 3.48 (2H, q, J 5.8 Hz), 6.33 (1H, t, J 6.0 Hz), 7.27 (3H, m), 7.40 (3H, m), 8.06 (1H, d, J 3.1 Hz), 8.21 (1H, d, J 3.1 Hz), 8.32 (1H, d, J 5.5 Hz) and 8.67 (1H, s); Retention time 4.32min (80:20). 136 NMR δ_(H) (400 MHz, DMSO) 1.08-1.32 (6H, m), 1.51-1.85 (4H, m), 3.53 (2H, m), 3.62 (3H, m), 7.29 (2H, m), 7.36 (1H, m), 8.08 (1H, d, J 3.1 Hz), 8.22 (1H, d, J 3.1 Hz) and 8.31 (1H, d, J 5.5 Hz); Retention time 3.58min. (80:20). 137 NMR δ_(H) (400 MHz, DMSO) 3.60 (2H, m), 3.79 (2H, m), 7.07 (1H, t, J 6.0 Hz), 7.26 (3H, m), 7.36 (2H, m), 7.42 (1H, m), 7.83 (1H, br s), 8.07 (1H, d, J 3.2 Hz), 8.22 (1H, d, J 3.2 Hz), 8.32 (1H, d, J 5.5 Hz) and 9.58 (1H, br s); Retention time 2.98min (80:20). 138 99 NMR δ_(H) (400 MHz, DMSO) 3.59 (2H, q, J 6.0 Hz), 3.78 (2H, m), 7.25 (1H, d, J 5.5 Hz), 7.29 (2H, d, J 9.1 Hz), 7.41 (1H, m), 7.42 (2H, d, J 9.0 Hz), 7.95 (1H, m), 8.07 (1H, d, J 3.5 Hz), 8.21 (1H, d, J 3.0 Hz), 8.32 (1H, d, J 5.5 Hz) and 9.63 (1H, br s); Retention time 3.98min (80:20) 139 93 IR ν_(max) (Nujol)/cm⁻¹ 3063, 2926, 2855, 1547, 1530, 1466; NMR δ_(H) (400 MHz, CDCl₃) 1.55 (9H, s), 7.56 (1H, d, J 7.5 Hz), 7.58 (1H, d, J 3.1 Hz), 8.60 (1H, d, J 7.5 Hz), 8.18 (1H, d, J 3.1 Hz). 140 13 IR ν_(max) (Nujol)/cm⁻¹ 3061, 2924, 1550, 1531, 1480; NMR δ_(H) (400 MHz, CDCl₃) 1.10 (2H, m), 1.24 (2H, m), 2.39 (1H, m), 7.42 (1H, d, J 7.5 Hz), 7.58 (1H, d, J 3.1 Hz), 8.00 (1H, d, J 7.5 Hz), 8.10 (1H, d, J 3.1 Hz). 141 65 mp 74.7-74.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 2925, 1531, 1455, 1350, 1078, and 799; NMR δ_(H) (400 MHz, CDCl₃) 1.52 (3H, t, J 7.5 Hz), 2.74 (3H, s), 3.19 (2H, q, J 7.5 Hz), 7.29 (1H, d, J 7.5 Hz), 7.52 (1H, d, J 6.0 Hz), 7.80 (1H, t, J 8.0 Hz), 8.06 (1H, d, J 5.5 Hz) and 8.58 (1H, d, J 8.0 Hz) 142 NMR δ_(H) (400 MHz, DMSO) 8.32 (1H, m), 8.22 (1H, m), 8.08 (1H, m), 7.79 (1H, m), 7.34-7.26 (2H, m), 3.45-3.29 (4H, m), 2.19 (1H, m) and 1.81-1.15 (10H, m); Retention time 3.26min, (80:20). 143 NMR δ_(H) (400 MHz, DMSO) 8.59 (1H, br s), 8.33 (1H, m), 8.22 (1H, m), 8.08 (1H, m), 7.94 (1H, m), 7.85 (2H, m), 7.63 (1H, m), 7.52-7.43 (1H, m), 7.28 (1H, m) and 3.60-3.37 (4H, br m); Retention time 3.03min, (80:20). 144 NMR δ_(H) (400 MHz, DMSO) 8.66 (1H, br s), 8.33 (1H, m), 8.22 (1H, m), 8.08 (1H, m), 7.88 (2H, m), 7.52 (2H, m), 7.45 (1H, br s), 7.27 (1H, m), 3.59-3.54 (2H, br m) and 3.30-3.20 (2H, m); Retention time 3.95min, (80:20). 145 70 NMR δ_(H) (400 MHz, DMSO) 3.36 (2H, q, J 6.0 Hz), 3.46 (2H, q, J 6.0 Hz), 7.12 (1H, dd, J 4.0, 5.0 Hz), 7.26 (1H, d, J 5.5 Hz), 7.72 (1H, m), 7.88 (1H, d, J 5.0 Hz), 8.07 (1H, d, J 3.0 Hz), 8.21 (1H, d, J 3.5 Hz), 8.32 (1H, d, J 5.5 Hz) and 8.60 (1H, m); Retention time 2.98min (80:20) 146 45 NMR δ_(H) (400 MHz, DMSO) 3.34 (2H, q, J 6.0 Hz), 3.53 (2H, q, J 6.0 Hz), 7.22-7.40 (8H, m), 8.08 (1H, d, J 3.0 Hz), 8.22 (1H, d, J 3.0 Hz) and 8.33 (1H, d, J 5.5 Hz); Retention time 3.08min (80:20) 147 62 NMR δ_(H) (400 MHz, DMSO) 3.28 (2H, q, J 6.0 Hz), 3.46 (2H, q, J 6.0 Hz), 5.01 (2H, s), 7.22-7.38 (8H, m), 8.07 (1H, d, J 3.0 Hz), 8.21 (1H, d, J 3.5 Hz) and 8.32 (1H, d, J 5.5 Hz); Retention time 3.39min (80:20) 148 29 NMR δ_(H) (400 MHz, DMSO) 2.92 (3H, s), 3.22 (2H, q, J 6.0 Hz), 3.51 (2H, q, J 6.0 Hz), 7.14 (1H, t, J 5.9 Hz), 7.31 (1H, d, J 5.5 Hz), 7.35 (1H, m), 8.08 (1H, d, J 3.5 Hz), 8.22 (1H, d, J 3.5 Hz) and 8.34 (1H, d, J 5.5 Hz); Retention time 2.36min (80:20) 149 70 NMR δ_(H) (400 MHz, DMSO) 0.83 (3H, t, J 7.5 Hz), 1.32 (2H, m), 1.60 (2H, m), 2.99 (2H, m), 3.20 (2H, q, J 6.0 Hz), 3.49 (2H, q, J 6.0 Hz), 7.15 (1H, t, J 5.9 Hz), 7.26 (1H, d, J 5.6 Hz), 7.32 (1H, m), 8.08 (1H, d, J 3.0 Hz), 8.22 (1H, d, J 3.0 Hz) and 8.33 (1H, d, J 5.5 Hz); Retention time 2.82min (80:20) 150 22 NMR δ_(H) (400 MHz, CDCl₃) 1.34 (3H, d, J 6.5 Hz), 3.71 (1H, dd, J 6.7, 10.7 Hz), 3.85 (1H, dd, J 3.0, 11.0 Hz), 4.29 (1H, m), 5.20 (1H, d, J 6.5 Hz), 7.22 (1H, d, J 5.5 Hz), 7.56 (1H, d, J 3.5 Hz), 7.95 (1H, d, J 5.5 Hz) and 8.11 (1H, d, J 3.0 Hz); Retention time 2.67min (80:20) 151 33 NMR δ_(H) (400 MHz, CDCl₃) 2.21 (2H, quintet, J 6.7 Hz), 3.59 (2H, q, J 6.5 Hz), 4.12 (2H, t, J 7.0 Hz), 5.20 (1H, t, J 6.0 Hz), 6.98 (1H, m), 7.09 (1H, m), 7.24 (1H, d, J 5.5 Hz), 7.55 (1H, m), 7.56 (1H, d, J 3.0 Hz), 7.97 (1H, d, J 5.5 Hz) and 8.12 (1H, d, J 3.0 Hz); Retention time 2.65min (80:20) 152 64 NMR δ_(H) (400 MHz, CDCl₃) 1.80 (1H, m), 1.97 (1H, m), 2.03 (1H, m), 2.20 (1H, m), 3.71-3.80 (2H, m), 3.85-3.97 (2H, m), 4.41 (1H, m), 7.23 (1H, d, J 5.5 Hz), 7.57 (1H, d, J 3.0 Hz), 7.94 (1H, d, J 5.5 Hz) and 8.12 (1H, d, J 3.0 Hz); Retention time 3.63min (80:20) 153 23 Mp 221.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3069, 2923, 2854, 1539, 1523, 1465, 1377, 1366 and 1319; NMR δ_(H) (400 MHz, CDCl₃) 8.16 (2H, m), 8.10 (1H, m), 7.64 (1H, m), 7.58 (1H, m), 7.50 (1H, m) and 7.20 (1H, m). 154 50 IR ν_(max) (Nujol)/cm⁻¹ 3074, 2924, 1546, 1529, 1473 and 1350; NMR δ_(H) (400 MHz, CDCl₃) 3.60 (2H, m), 4.15 (2H, m), 7.42 (1H, d, J 7.5 Hz), 7.58 (1H, d, J 3.1 Hz), 8.1 (1H, d, J 7.5 Hz), 8.15 (1H, d, J 3.1 Hz). 155 67 mp 300° C. dec; IR ν_(max) (Nujol)/cm⁻¹ 3472, 3051, 2925, 2853, 1707, 1598, 1525, 1466, 791, 742, 506; NMR δ_(H) (400 MHz, DMSO) 6.91 (1H, dd J 1.7, 3.6 Hz), 7.75 (1H, d, J 5.5 Hz), 7.82 (1H, br), 7.89 (1H, dd, J 0.8, 3.6 Hz), 8.23 (1H, dd, J 0.8, 1.7 Hz), 8.40 (1H, br), 8.64 (1H, d, J 5.5 Hz). 156 Mp 117.7-118.2° C.; IR ν_(max) (Nujol)/cm⁻¹ 3062, 2924, 2854, 1545, 1528, 1517, 1465, 1378, 1239 and 1134; NMR δ_(H) (400 MHz, CDCl₃) 8.39 (1H, m), 8.08 (1H, d, J 5.5 Hz), 7.98 (1H, dd, J 5.1, 1.1 Hz), 7.55 (1H, d, J 5.5 Hz) and 7.52 (1H, dd, J 5.1, 2.8 Hz); Anal Calcd for C₁₀H₅ClN₂S₂ 0.5 H₂O: C45.89; H, 2.31; N, 10.70. Found C, 45.48; H, 2.18; N, 10.53. 157 84 Mp 119.0-119.4° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924, 2854, 1557, 1524, 1468, 1388, 1334, 1279, 1234 and 1092; NMR δ_(H) (400 MHz, CDCl₃) 8.23 (1H, dd, J 2.9, 1.3 Hz), 7.95 (1H, dd, J 5.0, 1.0 Hz), 7.45 (1H, dd, J 5.1, 3.0 Hz), 7.27 (1H, m) and 3.31 (6H, s). Anal Calcd for C₁₂H₁₁N₃S₂: C, 55.15; H, 4.24; N, 16.07. Found: C55.36; H, 4.22; N, 16.05 158 28 Mp 146.5-147.2° C.; IR ν_(max) (Nujol)/cm⁻¹ 3054, 2925, 2854, 1537, 1516, 1495, 1467, 1365, 1244 and 1138; NMR δ_(H) (400 MHz, CDCl₃) 8.20 (2H, m), 8.11 (1H, d, J 5.6 Hz), and 7.62-7.57 (4H, m); Anal Calcd for C₁₂H₇ClN₂S 0.25 H₂O; C, 57.37; H, 3.01; N, 11.15. Found: C, 57.25; H, 2.84; N, 11.40. 159 97 Mp 112.9-114.1° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924, 2854, 1585, 1556, 1523, 1468, 1409, 1355 and 1241, NMR δ_(H) (400 MHz, CDCl₃) 8.18 (2H, m), 7.80 (1H, d, J 5.5 Hz), 7.56-7.51 (3H, m), 7.29 (1H, d, J 5.5 Hz) and 3.33 (6H, s). Anal. Calcd for C₁₄H₁₃N₃S 0.1 H₂O: C, 65.39; H, 5.13; N, 16.45; Found: C, 65.18; H, 5.14; N, 16.16. 160 33 Mp 129.3-129.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3117, 2955, 2924, 2854, 1576, 1542, 1527, 1512, 1472, 1382, 1264, 1243, 1226, 1184 and 1155, NMR δ_(H) (400 MHz, CDCl₃) 8.40 (1H, s), 8.05 (1H, d, J 5.5 Hz), 7.62 (1H, m), 7.54 (1H, d, J 5.5 Hz), and 7.22 (1H, m); Anal. Calcd for C₁₀H₅ClN₂OS: C, 50.75; H, 2.13; N, 11.83. Found: C, 50.71; H, 2.13; N, 11.72. 161 50 Mp 98.4-99.0° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924, 2854, 1562, 1540, 1527, 1463, 1404, 1381, 1348 and 1229, NMR δ_(H) (400 MHz, CDCl₃) 8.27 (1H, d, J 1.2 Hz), 7.76 (1H, d, J 5.4 Hz), 7.55 (1H, m), 7.26 (1H, m), 7.17 (1H, d, J 1.2 Hz), and 3.28 (6H, s); Anal Calcd. for C₁₂H₁₁N₃OS 0.1 H₂O: C, 58.33; H, 4.57; N, 17.01. Found: C, 58.59; H, 4.56; N, 16.69. 162 31 Mp 204.0-204.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 2926, 2854, 1590, 1526, 1494, 1465, 1377, 1335 and 1268, NMR δ_(H) (400 MHz, DMSO) 8.71 (1H, s), 8.33 (1H, d, J 1.2 Hz), 7.76 (1H, d, J 4.1 Hz), and 6.95 (1H, dd, J 3.8, 1.8 Hz): Anal Calcd for C₁₀H₄ClN₃O₃S 0.1 H₂O: C, 42.37; H, 1.49; N, 14.82. Found: C, 42.01; H, 1.42; N, 14.75. 163 69 IR ν_(max) (Nujol)/cm⁻¹ 2924, 2854, 1585, 1547, 1529, 1463, 1377 and 1154; NMR δ_(H) (400 MHz, CDCl₃) 8.39 (1H, m), 7.95 (1H, m), 7.62 (1H, m), 7.53 (1H, m), 7.24 (1H, m), 3.10 (2H, d, J 7.0 Hz) and 1.42 (3H, t, J 7.0 Hz); M/Z 231 (M + H)⁺. 164 41 IR ν_(max) (Nujol)/cm⁻¹ 2925, 2854, 1615, 1546, 1526, 1482, 1463, 1420 and 1376; NMR δ_(H) (400 MHz, CDCl₃) 8.00 (1H, m), 7.58 (1H, m), 3.18 (2H, m), 2.50 (3H, s), 2.39 (3H, s) and 1.43 (3H, m); M/Z 260 (M + H)⁺. 165 IR ν_(max) (Nujol)/cm⁻¹ 3093, 2955, 2924, 2854, 1589, 1572, 1538, 1522, 1467 and 1253. NMR δ_(H) (400 MHz, CDCl₃) 9.45 (1H, d, J 2.0 Hz), 8.85 (1H, m), 8.54-8.51 (1H, m), 8.18 (1H, d, J 5.5 Hz), 7.62 (1H, d, J 5.5 Hz), 7.56-7.53 (1H, m). 166 IR ν_(max) (Nujol)/cm⁻¹ 3056, 2925, 2854, 1580, 1557, 1524, 1467, 1361 and 1249. NMR δ_(H) (400 MHz, CDCl₃) 9.43 (1H, d, J 1.8 Hz), 8.76 (1H, dd, J 4.7, 1.5 Hz), 8.48-8.45 (1H, m), 7.83 (1H, d, J 5.5 Hz), 7.53-7.46 (1H, m), 7.32 (1H, d, J 5.5 Hz), 3.32 (6H, s). 167 NMR δ_(H) (400 MHz, CDCl₃) 8.12 (1H, d, J 5.5 Hz), 7.49 (1H, d, J 5.5 Hz), 7.38 (1H, s), 7.16 (1H, s), 7.30 (3H, s). 168 NMR δ_(H) (400 MHz, CDCl₃) 7.86 (1H, d, J 5.5 Hz), 7.31 (1H, s), 7.24 (1H, d, J 5.5 Hz), 7.06 (1H, s), 4.28 (3H, s), 3.29 (6H, s). 169 IR ν_(max) (Nujol)/cm⁻¹ 3332, 3072, 2924, 2854, 1606, 1547, 1516, 1489, 1464, 1409, 1387 and 1261; NMR δ_(H) (400 MHz, CDCl₃) 7.87 1H, d, J 5.5 Hz), 7.64 (1H, d, J 1.5 Hz), 7.23 (1H, d, J 5.5 Hz), 6.57 (1H, d, J 1.5 Hz), 5.79 (1H, t, J 7.0 Hz), 4.83 (2H, d, J 7.0 Hz), 3.28 (6H, s). 170 IR ν_(max) (Nujol)/cm⁻¹ 3443, 3218, 3122, 2954, 2925, 2854, 1560, 1532, 1513, 1484, 1457, 1389 and 1318; NMR δ_(H) (400 MHz, CDCl₃) 7.90 (1H, dd, J 5.5, 1.8 Hz), 7.30 (1H, s), 7.20 (1H, dd, J 5.5, 1.8 Hz), 7.06 (1H, s), 5.46 (1H, br s), 4.22 (3H, s), 3.91-3.90 (2H, m), 3.72-3.68 (3H, m). 171 IR ν_(max) (Nujol)/cm⁻¹ 3267, 3124, 2924, 2854, 1609, 1547, 1514, 1487, 1459, 1378; NMR δ_(H) (400 MHz, CDCl₃) 7.91 (1H, d, J 5.5 Hz), 7.65 (1H, s), 7.21 (1H, d, J 5.5 Hz), 6.56 (1H, s), 6.20 (1H, br s), 5.50 (1H, br s), 4.79 (2H, s), 3.90-3.88 (2H, m), 3.70-3.66 (2H, m), 1.61 (1H, br s). 172 IR ν_(max) (Nujol)/cm⁻¹ 2925, 2854, 1546, 1528, 1517, 1465, 1377 and 1222; NMR δ_(H) (400 MHz, CDCl₃) 8.12 (1H, d, J 5.5 Hz), 7.50 (1H, d, J 5.5 Hz), 7.38 (1H, s), 7.20 (1H, s), 4.80 (2H, q, J 7.0 Hz), 1.55 (3H, t, J 7.0 Hz). 173 IR ν_(max) (Nujol)/cm⁻¹ 3041, 2926, 2855, 1563, 1528, 1511, 1478, 1460, 1392 and 1377; NMR δ_(H) (400 MHz, CDCl₃) 7.86 (1H, d, J 5.5 Hz), 7.32 (1H, s), 7.23 (1H, d, J 5.5 Hz), 7.11 (1H, s), 4.83 (1H, q, J 7.0 Hz), 3.28 (6H, s), 1.52 (3H, t, J 7.0 Hz), 174 IR ν_(max) (Nujol)/cm⁻¹ 3458, 3334, 2925, 2855, 1560, 1516, 1480, 1466, 1427 and 1334; NMR δ_(H) (400 MHz, CDCl₃) 7.90 (1H, d, J 5.5 Hz), 7.32 (1H, s), 7.19 (1H, d, J 5.5 Hz), 7.11 (1H, s), 5.45 (1H, br t, J 5.5 Hz), 4.74 (2H, q, J 7.0 Hz), 3.91-3.89 (2H, m), 3.71-3.67 (2H, m), 1.52 (3H, t, J 7.0 Hz). 175 IR ν_(max) (Nujol)/cm⁻¹ 3069, 2954, 2925, 2854, 1548, 1531, 1517, 1467, 1408, 1249 and 1225; NMR δ_(H) (400 MHz, CDCl₃) 8.19 (1H, d, J 5.5 Hz), 7.54 (1H, d, J 5.5 Hz), 7.47-7.41 (2H, m), 6.22 (2H, s), 3.76 (2H, t, J 8.5 Hz), 1.02 (2H, t, J 8.5 Hz). 176 Mp 131-132° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924, 2854, 1560, 1533, 1512, 1480, 1465, 1419, 1389, 1250 and 1089; NMR δ_(H) (400 MHz, CDCl₃) 7.95 (1H, d, J 5.5 Hz), 7.43 (1H, d, J 1.5 Hz), 7.38 (1H, d, J 1.5 Hz), 7.30 (1H, d, J 5.5 Hz), 6.28 (2H, s), 3.66 (2H, t, 8.0 Hz), 3.36 (6H, s), 0.97 (3H, t, J 8.0 Hz). 177 Mp 209-210° C.; IR ν_(max) (Nujol)/cm⁻¹ 2925, 2854, 1749, 1559, 1530, 1508, 1476, 1388, 1376, 1241 and 1214; NMR δ_(H) (400 MHz, CDCl₃) 7.88 (1H, d, J 5.5 Hz), 7.37 (1H, d, J 1.0 Hz), 7.21 (1H, d, J 5.5 Hz), 7.08 (1H, d, J 1.5 Hz), 5.61 (2H, s), 4.18 (2H, q, J 7.5 Hz), 3.24 (6H, s), 1.18 (3H, t, J 7.0 Hz). 178 Mp 162.2-164.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 3365, 2924, 2854, 1559, 1528, 1512, 1465, 1389, 1378, 1336, and 1236; NMR δ_(H) (400 MHz, CDCl₃) 7.89 (1H, d, J 5.5 Hz), 7.34 (1H, d, J 1.0 Hz), 7.22 (1H, d, J 5.5 Hz), 7.19 (1H, d, J 1.0 Hz), 4.94 (2H, t, J 5.0 Hz), 4.09 (2H, br q, J 5.0 Hz), 3.26 (6H, s), 2.50 (1H, br t, J 5.0 Hz). 179 Mp 69-70° C.; IR ν_(max) (Nujol)/cm⁻¹ 3090, 2925, 2854, 1542, 1514, 1477, 1376, 1336, 1221 and 1109; NMR δ_(H) (400 MHz, CDCl₃) 8.04 (1H, d, J 5.5 Hz), 7.50 (1H, d, J 5.5 Hz), 7.40 (1H, d, J 1.0 Hz), 7.34 (1H, d, J 1.0 Hz), 6.29 (2H, s), 3.40 (3H, s), 3.15 (2H, q, 7.5 Hz), 1.49 (3H, t, 7.5 Hz). 180 Mp <100° C.; IR ν_(max) (Nujol)/cm⁻¹ 2953, 2925, 2854, 1547, 1514, 1495, 1458, 1378, 1316, 1248 and 1095; NMR δ_(H) (400 MHz, CDCl₃) 8.17 (1H, s), 8.10 (1H, d, J 5.5 Hz), 7.56 (1H, d, J 5.5 Hz), 6.41 (2H, s), 3.73 (2H, t, J 8.0 Hz), 3.20 (2H, q, J 7.5 Hz), 1.50 (3H, t, J 8.0 Hz), 0.90 (2H, t, J 8.0 Hz), 0.09 (9H, s). 181 Mp 108-109° C.; IR ν_(max) (Nujol)/cm⁻¹ 3076, 2954, 2923, 2854, 1571, 1537, 1519, 1443, 1400, 1249, 1129 and 1116; NMR δ_(H) (400 MHz, CDCl₃) 8.49 (1H, s), 8.38 (1H, s), 8.05 (1H, d, J 5.5 Hz), 7.54 (1H, d, J 5.5 Hz), 5.55 (2H, s), 3.66 (2H, t, J 8.0 Hz), 0.96 (2H, t, J 8.5 Hz), 0.00 (9H, s). 182 Mp 141-142° C.; IR ν_(max) (Nujol)/cm⁻¹ 2925, 2854, 1545, 1522, 1462, 1378 and 1225; NMR δ_(H) (400 MHz, CDCl₃) 8.10 (1H, d, J 5.5 Hz), 7.65 (1H, d, J 2.0 Hz) 7.57 (1H, d, J 5.5 Hz), 7.11 (1H, d, J 2.0 Hz), 4.37 (3H, s). 183 Mp 60-61° C.; IR ν_(max) (Nujol)/cm⁻¹ 2924, 2854, 1579, 1556, 1458, 1404, 1377, 1278, 1247 and 1100; NMR δ_(H) (400 MHz, CDCl₃) 8.36 (1H, s), 8.32 (1H, s), 7.77 (1H, d, J 5.5 Hz), 7.27 (1H, d, J 5.5 Hz), 5.53 (2H, s), 3.66 2H, t, J 8.5 Hz) 3.30 (6H, s), 0.96 (3H, t, J 8.0 Hz), 0.00 (9H, s). 184 Mp 126.5-127° C.; IR ν_(max) (Nujol)/cm⁻¹ 3052, 2954, 2924, 2854, 1553, 1515, 1465, 1412, 1386, 1353 and 1232; NMR δ_(H) (400 MHz, CDCl₃) 7.80 (1H, d, J 5.5 Hz), 7.60 (1H, d, J 2.0 Hz), 7.27 (1H, d, J 5.5 Hz), 7.01 (1H, d, J 2.0 Hz), 4.34 (3H, s), 3.29 (6H, s). 185 Mp 210-211° C.; IR ν_(max) (Nujol)/cm⁻¹ 3146, 3090, 3058, 2924, 2854, 1582, 1556, 1465, 1404, 1377, 1277 and 1236; NMR δ_(H) (400 MHz, CDCl₃) 10.47 (1H, br s), 8.39 (2H, s), 7.77 (1H, d, J 5.5 Hz), 7.33-7.23 (1H, d, J 5.5 Hz), 3.30 (6H, s). 186 Mp 175.4-175.9° C.; IR ν_(max) (Nujol)/cm⁻¹ 2925, 2854, 1548, 1458, 1407, 1383, 1279 and 1228; NMR δ_(H) (400 MHz, CDCl₃) 8.25 (1H, s), 8.15 (1H, s), 7.75 (1H, d, J 5.5 Hz), 7.25 (1H, d, J 5.5 Hz), 4.02 (3H, s), 3.29 (6H, s), 187 Mp 110.2-111.4° C.; NMR δ_(H) (400 MHz, CDCl₃) 8.10 (1H, d, J 5.5 Hz), 7.56 (1H, d, J 5.5 Hz), 7.26 (1H, s), 4.58 (3H, s), 3.20 (2H, q, J 7.5 Hz), 1.50 (3H, t, J 7.5 Hz). 188 Mp 104.7-104.8° C.; IR ν_(max) (Nujol)/cm⁻¹ 3095, 2926, 2854, 1595, 1552, 1532, 1505, 1483, 1458, 1434, 1377, 1349 and 1302; p NMR δ_(H) (400 MHz, CDCl₃) 7.45 (1H, d, J 3.5 Hz), 7.26 (1H, s), 7.15 (1H, d, J 1.5 Hz), 6.64 (1H, dd, J 3.5 Hz, 2.0 Hz), 3.08 (2H, q, J 7.5 Hz), 2.69 (3H, s), 1.45 (3H, t, J 7.5 Hz).

Adenosine Receptor Binding

Binding Affinities at hA_(2A) Receptors

The compounds were examined in an assay measuring in vitro binding to human adenosine A_(2A) receptors by determining the displacement of the adenosine A_(2A) receptor selective radioligand [³ H]-CGS 21680 using standard techniques. The results are summarised in Table 3.

TABLE 3 Example K_(i) (nM) Example 15 11 Example 40 19 Example 65 2 Example 70 4 Example 71 8 Example 76 1 Example 79 14 Example 80 1 Example 82 2 Example 89 20 Example 104 5 Example 105 6 Example 110 35 Example 111 2 Example 113 1 Example 139 3 Example 140 2 Example 141 9 Example 152 3 Example 154 6

Evaluation of Potential Anti-Parkinsonian Activity In Vivo Haloperidol-Induced Hypolocomotion Model

It has previously been demonstrated that adenosine antagonists, such as theophylline, can reverse the behavioural depressant effects of dopamine antagonists, such as haloperidol, in rodents (Mandhane S. N. et al., Adenosine A₂ receptors modulate haloperidol-induced catalepsy in rats. Eur. J. Pharmacol. 1997, 328, 135-141). This approach is also considered a valid method for screening drugs with potential antiparkinsonian effects. Thus, the ability of novel adenosine antagonists to block haloperidol-induced deficits in locomotor activity in mice can be used to assess both in vivo and potential antiparkinsonian efficacy.

Method

Female TO mice (25-30 g) obtained from TUCK, UK, are used for all experiments. Animals are housed in groups of 8 [cage size—40 (width)×40 (length)×20 (height)cm] under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity (55±15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.

Drugs

Liquid injectable haloperidol (1 ml Serenance ampoules from Baker Norton, Harlow, Essex, each containing haloperidol BP 5 mg, batch #P424) are diluted to a final concentration of 0.02 mg/ml using saline. Test compounds are typically prepared as aqueous suspensions in 8% Tween. All compounds are administered intraperitoneally in a volume of 10 ml/kg.

Procedure

1.5 hours before testing, mice are administered 0.2 mg/kg haloperidol, a dose that reduces baseline locomotor activity by at least 50%. Test substances are typically administered 5-60 minutes prior to testing. The animals are then placed individually into clean, clear polycarbonate cages [20 (width)×40 (length)×20 (height) cm, with a flat perforated, Perspex lid]. Horizontal locomotor activity is determined by placing the cages within a frame containing a 3×6 array of photocells linked to a computer, which tabulates beam breaks. Mice are left undisturbed to explore for 1 hour, and the number of beams breaks made during this period serves as a record of locomotor activity which is compared with data for control animals for statistically significant differences.

6-OHDA Model

Parkinson's disease is a progressive neurodegenerative disorder characterised by symptoms of muscle rigidity, tremor, paucity of movement (hypokinesia), and postural instability. It has been established for some time that the primary deficit in PD is a loss of dopaminergic neurones in the substantia nigra which project to the striatum, and indeed a substantial proportion of striatal dopamine is lost (ca 80-85%) before symptoms are observed. The loss of striatal dopamine results in abnormal activity of the basal ganglia, a series of nuclei which regulate smooth and well co-ordinated movement (Blandini F. et al., Glutamate and Parkinson's Disease. Mol. Neurobiol. 1996, 12, 73-94). The neurochemical deficits seen in Parkinson's disease can be reproduced by local injection of the dopaminergic neurotoxin 6-hydroxydopamine into brain regions containing either the cell bodies or axonal fibres of the nigrostriatal neurones.

By unilaterally lesioning the nigrostriatal pathway on only one-side of the brain, a behavioural asymmetry in movement inhibition is observed. Although unilaterally-lesioned animals are still mobile and capable of self maintenance, the remaining dopamine-sensitive neurones on the lesioned side become supersensitive to stimulation. This is demonstrated by the observation that following systemic administration of dopamine agonists, such as apomorphine, animals show a pronounced rotation in a direction contralateral to the side of lesioning. The ability of compounds to induce contralateral rotations in 6-OHDA lesioned rats has proven to be a sensitive model to predict drug efficacy in the treatment of Parkinson's Disease.

Animals

Male Sprague-Dawley rats, obtained from Charles River, are used for all experiments. Animals are housed in groups of 5 under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity (55±15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.

Drugs

Ascorbic acid, desipramine, 6-OHDA and apomorphine (Sigma-Aldrich, Poole, UK). 6-OHDA is freshly prepared as a solution in 0.2% ascorbate at a concentration of 4 mg/mL prior to surgery. Desipramine is dissolved in warm saline, and administered in a volume of 1 ml/kg. Apomorphine is dissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg. Test compounds are suspended in 8% Tween and injected in a volume of 2 mL/kg.

Surgery

15 minutes prior to surgery, animals are given an intraperitoneal injection of the noradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damage to non-dopamine neurones. Animals are then placed in an anaesthetic chamber and anaesthetised using a mixture of oxygen and isoflurane. Once unconscious, the animals are transferred to a stereotaxic frame, where anaesthesia is maintained through a mask. The top of the animal's head is shaved and sterilised using an iodine solution. Once dry, a 2 cm long incision is made along the midline of the scalp and the skin retracted and clipped back to expose the skull. A small hole is then drilled through the skill above the injection site. In order to lesion the nigrostriatal pathway, the injection cannula is slowly lowered to position above the right medial forebrain bundle at −3.2 mm anterior posterior, −1.5 mm medial lateral from bregma, and to a depth of 7.2 mm below the duramater. 2 minutes after lowing the cannula, 2 μL of 6-OHDA is infused at a rate of 0.5 μL/min over 4 minutes, yielding a final dose of 8 μg. The cannula is then left in place for a further 5 minutes to facilitate diffusion before being slowly withdrawn. The skin is then sutured shut using Ethicon W501 Mersilk, and the animal removed from the stereotaxic frame and returned to its homecage. The rats are allowed 2 weeks to recover from surgery before behavioural testing.

Apparatus

Rotational behaviour is measured using an eight station rotameter system provided by Med Associates, San Diego, USA. Each station is comprised of a stainless steel bowl (45 cm diameter×15 cm high) enclosed in a transparent Plexiglas cover running around the edge of the bowl, and extending to a height of 29 cm. To assess rotation, rats are placed in cloth jacket attached to a spring tether connected to optical rotameter positioned above the bowl, which assesses movement to the left or right either as partial (45°) or full (360°) rotations. All eight stations are interfaced to a computer that tabulated data.

Procedure

To reduce stress during drug testing, rats are initially habituated to the apparatus for 15 minutes on four consecutive days. On the test day, rats are given an intraperitoneal injection of test compound 30 minutes prior to testing. Immediately prior to testing, animals are given a subcutaneous injection of a subthreshold dose of apomorphine, then placed in the harness and the number of rotations recorded for one hour. The total number of full contralateral rotations during the hour test period serves as an index of antiparkinsonian drug efficacy. 

1.-49. (canceled)
 50. A method for blocking a purine receptor in a subject, comprising administering to said subject an effective dose of a compound of formula (I):

wherein: X is S or O; R₁ is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR₅, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇, NR₆R₇, NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈, and NR₅SO₂R₈; R₂ is selected from aryl attached via an unsaturated carbon atom; R₃ is selected from the group consisting of H, alkyl, hydroxy, alkoxy, halogen, CN and NO₂; R₄ is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO₂, COR₅, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇, NR₆R₇, NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈ and NR₅SO₂R₈; R₅, R₆ and R₇ are independently selected from the group consisting of H, alkyl and aryl, or where R₆ and R₇ are in an (NR₆R₇) group, R₆ and R₇ may be linked to form a heterocyclic group, or where R₅, R₆ and R₇ are in a (CONR₅NR₆R₇) group, R₅ and R₆ may be linked to form a heterocyclic group; and R₈ is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof.
 51. The method according to claim 50, wherein the purine receptor is an adenosine receptor.
 52. The method according to claim 51, wherein the adenosine receptor is an A_(2A) receptor.
 53. The method according to claim 50, wherein the subject is human.
 54. A method for treating a subject suffering from or at risk of a condition selected from the group consisting of: (i) a movement disorder; (ii) an affective disorder; (iii) a central or peripheral nervous system degenerative disorder; (iv) schizophrenia or a related psychosis; (v) a cognitive disorder; (vi) an attention disorder; (vii) a central nervous system injury; (viii) cerebral ischaemia; (ix) myocardial ischaemis; (x) muscle ischaemia; (xi) a sleep disorder; (xii) an eye disorder selected from the group consisting of retinal ischaemia-reperfusion injury and diabetic neuropathy; (xiii) a cardiovascular disorder; (xiv) memory impairment; (xv) ADHD; (xvi) narcolepsy; and (xvii) diabetes and its complications, the method comprising administering to said subject an effective dose of a compound of formula (I):

wherein: X is S or O; R₁ is selected from the group consisting of _H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR₅, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇, NR₆R₇, NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈, and NR₅SO₂R₈; R₂ is selected from aryl attached via an unsaturated carbon atom; R₃ is selected from the group consisting of H, alkyl, hydroxy, alkoxy, halogen, CN and NO₂; R₄ is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO₂, COR₅, CO₂R₅, CONR₆R₇, CONR₅NR₆R₇, NR₆R₇, NR₅CONR₆R₇, NR₅COR₆, NR₅CO₂R₈ and NR₅SO₂R₈; R₅, R₆ and R₇ are independently selected from the group consisting of H, alkyl and aryl, or where R₆ and R₇ are in an (NR₆R₇) group, R₆ and R₇ may be linked to form a heterocyclic group, or where R₅, R₆ and R₇ are in a (CONR₅NR₆R₇) group, R₅ and R₆ may be linked to form a heterocyclic group; and R₈ is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof.
 55. The method according to claim 54, wherein the movement disorder is Parkinson's disease.
 56. The method according to claim 55, wherein the Parkinson's disease is selected from the group consisting of drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning and post-traumatic Parkinson's disease.
 57. The method according to claim 54, wherein the movement disorder is selected from the group consisting of progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, and other disorders of the basal ganglia which result in dyskinesias.
 58. The method according to claim 54, wherein the compound of formula (I) is administered in combination with one or more additional drugs useful in the treatment of movement disorders, and wherein the compound of formula (I) and the one or more additional drugs are in the same formulation or in separate formulations for simultaneous or sequential administration.
 59. The method according to claim 58, wherein the one or more additional drugs are effective in treating Parkinson's disease.
 60. The method according to claim 58, wherein the one or more additional drugs are selected from the group consisting of L-DOPA and a dopamine agonist.
 61. The method according to claim 54, wherein the subject is human. 